With the turn of the century, Guiding Light split away from centering itself in Springfield and substantially changed the focus of the entire series. Springfield was invaded by the Santos crime family and a baroque tale of battles for the throne and international intrigue dominated life on the distant island of San Cristobel.

The first half of the decade also saw the show go through many different writing teams and producers until Ellen Wheeler and David Kreizman arrived to offer relative stability, and substantial budget cuts, which led to the loss of many old characters and a deficit of new ones. The show's budget would continue to fall and it remained near the bottom of the ratings for the entire decade.

The Bauers nearly vanished early this decade, but not before the life histories of Ed, Alan, Billy and Buzz could all be substantially rewritten with the Maryanne Caruthers story. It wasn't the only rewriting being done. Reva's life was reinvented numerous times and her family life radically recast. By mid decade, much of the cast was either bumped into obscurity or killed off and those left behind were gradually broken up and re-paired among who was left. Plots of the decade concerned numerous child abductions, child molestation, rape, abortion, coup d'etats, election rigging, doppelgangers, the return of long-lost children, demonic children, reformed bad characters, religious revelations, heart transplants, cancer, time travel, murder, drug addiction, mob wars, corporate espionage, partner swapping, jewelry stealing, brain injuries, corrupt cops, pseudo-incestuous relationships, car accidents, drug trafficking, blackmail and sapphic love.

The decade also saw the series go through some of its most radical shifts in terms of style and structure. Breaking in many ways from the tradition which it had invented, the show experimented with new ways of telling stories using special episodes examining single characters and new digital technologies. Toward the end, the series also became far more self-referential and seemed to be trying to return to its more socially conscious roots and more intimate storytelling. Nonetheless, with ratings still in decline, the series was canceled. After 72 years, Guiding Light aired its final episode on September 18, 2009.