Dr. Howard Sheinfeld is the charismatic head physician at the Clark St. Emergency Room in Chicago. Having recently finalized his second divorce, Dr. Sheinfeld is more than willing to pull a 48 hour shift instead of cooling his heels at home. The Clark St. staff welcomes their new, no-nonsense boss Dr. Eve Sheridan. Her strict policy changes clash with Dr. Sheinfeld's laid-back style and the two must learn to work together peacefully. Meanwhile, George Jefferson himself visits the hospital to see his niece Nurse Julie Williams.
Dr. Sheridan tries to save a patient from himself when he leaves the hospital despite having chest pains. The arrival of a stabbing victim shakes up the E/R and Dr. Sheinfeld believes their John Doe is a lost cause. In a race against the clock, Dr. Sheridan desperately tries to save their patient in time for the surgical team to arrive.
Dr. Sheridan's sister Karen is in town to help decide if their father should be put in a nursing home. Howard tries his hardest to put the moves on Karen but Eve warns him to stay away. Meanwhile, an unconscious young boy is brought into the E/R and the staff suspects child abuse.
Medical and moral ethics come into question when a cancer patient in severe pain asks Dr. Sheinfeld to let him die. Eve discovers that a patient is transgender and Nurse Thor's marital troubles reach a breaking point.
Dr. Sheridan is put in an awkward position when the hospital administrator tells her to fire Howard in order to cut costs. Howard's son David turns up in the emergency room with blue hair and a friend unconscious from a drug overdose. While handling a nasty motorcycle accident involving a teen boy, Howard reevaluates his relationship with his wayward son.
Dr. Sheinfeld's second ex-wife Phyllis tries to make amends when she suspects she is pregnant. Eve struggles with personal problems of her own when her devotion to the job gets in the way of an important dinner date with her boyfriend Robert.
Eve feels personally responsible when a patient unexpectedly dies after she promised his family that he would survive. Dr. Sheinfeld contemplates what it might be like to become a father again as he waits for his ex-wife Phyllis to give him the results of her pregnancy test.
Rumor has it that Dr. Sheinfeld is planning to resign his job at the E/R in order to accept a cushy position at a business firm. Dr. Sheridan is dismayed because she wants to hire Howard as their full-time specialist, even though she is required to interview other applicants. Meanwhile, the staff has their work cut out for them when a mentally ill patient attempts suicide and a young boy is brought in with a collapsed lung.
Howard decides to sell his old practice but has a difficult time finding the right person to trust with his former patients. The Emergency Room is on high alert when the bomb squad is called in to help remove an exploding bullet from a woman's arm.
Julie tries to convince Nurse Thor not to quit her job after Dr. Sheridan refuses to allow the Head Nurse to make minor medical decisions. Howard ends up in over his head when Nurse Cory admits she's in love with him. Meanwhile, the staff suspects a sick toddler in the E/R might be the victim of a kidnapping.
Dr. Sheinfeld starts a workout regimen after he begins dating a 23-year-old aerobics instructor. The staff can't help themselves from making fun of Howard for dating a woman so much younger than him. However, Eve can't help from flirting with a charismatic, yet much older patient named Paolo when he admits his attraction to her. Tension runs high in the E/R when Fred is injured while on-duty and Thor finds a baby abandoned in the hospital lobby.
Strange events plague the E/R during a full moon. Dr. Sheinfeld's diagnosis of an injured famous basketball star could mean the difference between winning or losing a big upcoming game. Additionally, Howard's father Morris pays a visit and Maria awaits a reunion with her own father whom she hasn't seen since she was a baby.
Eve suspects an extremely sick little boy might have meningitis but his family resists medical treatment because it is against their religion. Dr. Sheinfeld presses to treat him regardless but Eve fears the hospital could be sued. On top it all, Howard visits with an old army buddy whose life he saved in Vietnam and Nurse Thor receives flowers from a secret admirer.
Howard is being sued for malpractice, but is doubtful about calling Dr. Sheridan as a character witness when she refuses to shade the truth a little, and nurse Thor's nephew is hired as the emergency room's new EMT.
A blizzard strands the staff at the hospital overnight. When Julie's replacement can't make it in, she refuses to work overtime and miss a date with her new boyfriend. Dr. Sheridan fires her for leaving the E/R understaffed. Howard's daughter Jenny takes refuge at the hospital because she's upset that her mother is getting re-married. He agrees to think about letting Jenny move in with him.
Howard's first wife Sheila meets with him and Jenny in order to make the final decision about where Jenny is going to live. The E/R reluctantly welcomes an obnoxious new administrator named Howard Stickley. His frequently inappropriate comments and propositioning of female employees causes Dr. Sheridan to threaten to report him for sexual harassment. Ace tries to ask Dr. Sheridan out to dinner but she repeatedly turns him down.
The staff relaxes at Houlihan's, a local hangout near the hospital. Howard is looking forward to catching up with his younger brother Sam but becomes jealous when Sam develops a romantic interest in Dr. Sheridan. After much teasing from the staff, Eve has to set the record straight with Howard. Julie and Maria struggle to get along now that they have become roommates in order to save money.
Forced to work on a weekend, Howard moves his Saturday night poker game into the E/R lounge. Dr. Sheridan disapproves but relents when Howard promises to keep it quiet. Fred collapses during the game and finds out he has high blood pressure. Later, Howard hits the roof when Jenny tells him that "my place Ace" asked her out. But Jenny ends up crushed when she finds out that she mistook Ace's invitation to a concert for a date.
Dr. Sheinfeld is featured in the newspapers when word gets around that he's dating a wealthy socialite named Bitsy Carmichael. When both of his ex-wives arrive at the hospital to speak with him, Howard has to juggle their complaints with a busy night in the emergency room. Painters work on fixing up the E/R, which is a problem for Dr. Sheridan because she is allergic to paint. Nurse Thor turns to a specialist because of a serious concern about her health.
The entire staff offers their support to Nurse Thor after she receives frightening news about her health. Sheila and Phyllis, Howard's ex-wives, suspect that Dr. Sheridan and Howard might have feelings for each other. Both doctors deny it, but that doesn't stop the staff from teasing them. Two wounded firefighters and a young man high on LSD are brought in for care.
Arguments erupt in the E/R when Eve loses her life savings on a joint investment she made with Howard and Maria becomes jealous that Fred asked Julie to attend a banquet with him. Everything gets put into perspective when two thieves hold the staff at gunpoint.
Dr. Sheinfeld starts seeing private patients while at the E/R as a favor for a colleague. When Stickley finds out, he offers Howard an ultimatum: falsify Stickley's personal health form or get fired. The news that her close friend Lois is pregnant intensifies Eve's desire to have a baby of her own. Eve makes some serious decisions about the future, including her relationship with Howard.