Although Greene enjoys working the ER, his marriage has been strained by the many nights on call, the long hours, and his wife Jen's decision to complete law school.

In the pilot episode, which takes place on St. Patrick's Day 1994, Dr. Greene, the chief resident, is awakened in the first scene to help his long-time friend Doug, the emergency pediatric fellow who often comes in to sober up on his nights off.

During the same episode, Jen gets Mark to visit a private practice near the hospital to explore the possibility of leaving his job at the ER and getting more family-friendly hours.

As a newly admitted member of the bar, Jen has been clerking for a judge in Milwaukee and becomes increasingly tired of commuting and living separately to accommodate Greene's job.

In "Love's Labor Lost", Greene makes miscalculations in treating a pregnant woman that leads to her death in childbirth, and the after-effects of this case linger long into Season 2.

His love life takes another downward spin when his feelings for Dr. Lewis increase, but she leaves the hospital for a job in Phoenix, Arizona.

The attack is initially believed to have been carried out by Chris Law in retaliation to avenge the death of his brother, who had been treated by Dr. Greene for a gunshot wound.

Mark also finds out that his mother viewed his birth as a mistake, as she didn't know his father well and got married quickly when she got pregnant.

Ruth eventually dies and Mark goes to her funeral, leaving him on edge when he clashes with Kerry Weaver over Robert Romano's successful drive for the chief of staff position.

Father and son reach an emotional bonding that heals the difficult relationship from Mark's youth, and David eventually succumbs to his cancer.

Rachel's reckless behavior and drug use lead to Ella, still, an infant, overdosing in season 8, putting a heavy strain on Mark and Elizabeth's marriage.

Greene is told that the tumor is near a critical section of his brain but hasn't "invaded" it yet and they can perform an operation on New Year's Eve 2000.

While chemotherapy treatment will only allow Greene to live for another 5–6 months, Burke points out: "You should have been dead a year ago, Mark.

Though she vehemently denies it, her recreational drug use becomes apparent when her baby sister Ella gets hold of some ecstasy in her backpack and nearly dies after ingesting it in the episode "Damage is Done".

When Rachel shows up, Mark can barely control his anger at her, berating her for repeatedly for lying to him and for putting Ella in danger.

He leaves the ER, stops his chemotherapy treatments, tells John Carter that he will now "set the tone" and takes Rachel on a last-minute trip to Hawaii to rebuild his relationship with her and relive happier times.

Rachel tells her father that she remembers a lullaby that Mark used to sing her when she was a baby and slips a pair of headphones on his head and plays Israel Kamakawiwo'ole's rendition of "Over The Rainbow" for him as he smiles and falls back asleep.

At the close of the episode, as the staff rush out to the ambulance bay to handle incoming casualties, the wind blowing through the open door tears one page of Greene's letter off the bulletin board.

Many of his friends and colleagues come to the funeral: John Carter, Peter Benton, Kerry Weaver, Abby Lockhart, Luka Kovač, Susan Lewis, Jing-Mei Chen, Robert Romano, Jerry Markovic, Lydia Wright, Frank Martin, Donald Anspaugh, William "Wild Willy" Swift (played by Michael Ironside in 1994), Haleh Adams, Michael Gallant, Cleo Finch, Jen, Rachel, Ella, and Elizabeth.

Rachel then suddenly asks the driver to pull over: she walks to a bunch of balloons attached to a fence, takes a purple one, and slowly lets go of it, watching it rise toward the sky.

Rachel goes back to living with her mother in St. Louis but later returns to Chicago when the time comes to select a college, as well as asking a bemused Elizabeth to help her acquire effective birth control pills.

In the April 2009 ER series finale, Rachel returns to County General to interview for a position as a med student, showing that she has become a responsible young woman and followed in Mark's footsteps.

It was reported that Dr. Mark Greene was written out of the series because actor Anthony Edwards had decided that he wanted to move on to other opportunities and spend time with his family.

In the Season 12 episode "Body and Soul," he is mentioned during a flashback to 2002, when Dr. Pratt tells patient Nate Lennox (James Woods) that the reason the ER has few staff working is because they are at Greene's funeral.

In Season 14's "Blackout," Nurse Chuny Marquez expresses incredulity that the ER will be led by young physicians Dr. Pratt and Dr. Morris, versus Dr. Greene and Dr. Ross.

In 2008, ER producers announced that Edwards would reprise his role for the series' final season, with Dr. Greene appearing in flashbacks in the episode "Heal Thyself" shedding light on Dr. Catherine Banfield's (played by Angela Bassett) past.

The flashback episode took place in 2002, just months before Greene's death, and revealed an encounter he had with Catherine Banfield, six years before she began working in that same emergency room.

Darryl dies in the ER but it was Greene's heroic actions that triggered Catherine in the present day to help save a young girl from drowning and may have also inspired her to work full-time at County.