Launched in 1963, the first stories were mainly set at General Hospital in an unnamed mid-sized Eastern city (the name of the city, Port Charles, would not be mentioned until the 1970s), revolving around Dr. Steve Hardy (John Beradino) and his friend, Nurse Jessie Brewer (Emily McLaughlin). Steve was Chief of Internal Medicine on the hospital's seventh floor and dedicated his life to healing and caring for the sick, ably assisted by Nurse Jessie. Jessie's turbulent marriage to the much-younger Dr. Phil Brewer (originally portrayed by Roy Thinnes; lastly by Martin West) was the center of many early storylines.
The 1981 wedding of Luke and Laura, played by Anthony Geary and Genie Francis, was the most watched event in daytime serial history.
During the 1980s the series featured several high-profile action, adventure, and some science fiction based storylines.
In the 1990s, General Hospital entered a transitional phase as the action/adventure storylines of the 1980s became less popular. The show gained critical acclaim for its sensitive handling of social issues, most notable of which were the heart transplant storyline which involved the death of eight-year-old BJ Jones (daughter of Dr. Tony Jones and R.N. Bobbie Spencer) in a bus crash and the subsequent donation of her heart to her dying cousin Maxie Jones. Shortly afterwards, Monica Quartermaine (Leslie Charleson) began a long battle with breast cancer, which led to her adopting Emily Quartermaine, a young girl who had been orphaned when her mother died of breast cancer. Her adopted daughter was later murdered by an unknown killer, leaving Dr. Monica Quartermanine heartbroken. GH was also praised for yet another storyline in the form of the beautiful but tragic love story of teenagers Stone Cates (Michael Sutton) and Robin Scorpio (Kimberly McCullough). After a struggle that lasted throughout most of 1995, Stone died from AIDS at the age of 19 and his death was followed by storylines in which 17 year old Robin had to deal with being HIV-positive as a result of her and Stone's relationship. The storyline got Sutton a Daytime Emmy nomination for Outstanding Supporting Actor and won McCullough an Outstanding Younger Actress award.
On Saturday, December 14, 1996, General Hospital aired its one and only primetime episode, General Hospital: Twist of Fate, which picked up where that Friday's episode had left off. The special centered around Laura's supposed death at the hands of Stefan Cassadine.
The series' 11,000th episode aired on February 20, 2006.
On April 23, 2009, General Hospital became ABC's first regular daytime drama to be taped and broadcast in high definition, though the 2008 season of its primetime spin-off General Hospital: Night Shift was in high definition. This is the second daytime drama to move to high definition after CBS's The Young and the Restless.
On February 23, 2010, the series aired its 12,000th episode.