Margolis emerged as a star in the early days of the Internet. She was named Yahoo! Internet Life magazine's "Queen of the Internet" from 1996-1999. She also found her way into the 2000 Guinness Book of World Records as a result of being the "most downloaded" person in 1999 – a statistic that has no way of being accurately measured. At the age of 34, the peak of her popularity, Margolis was downloaded 70,000 times in a span of 24 hours.

On December 5, 2000, Danni Ashe beat Margolis' record. Guinness World Records awarded Danni Ashe the title "Most downloaded woman on the Internet" when they confirmed Danni's image had been downloaded over a billion times. Danni Ashe was the first person in history to officially reach this milestone.

In November 2005, Margolis teamed up with the World Poker Tour to become the new hostess for Chipleaders. In an April 2006 interview with The Washington Post, Margolis discussed her nude photo session for the December 2006 issue of Playboy, saying that she had posed for Playboy many times in the past, but never full frontal nude. She cited her good looks at age 40 and wanting to be an inspiration to mothers and women her age as the reason she chose to finally pose nude. "It will be fun to go up against the 20-year-olds and show them that they don't have anything on me!" she told the AP. In an interview with EXTRA she said that Desperate Housewives had been an inspiration for her as it showed that mothers her age can also be fit and sexy. Margolis' nude pictorial was published in the December 2006 issue of Playboy. A portion of the proceeds from issues sold will go to a charity for which Margolis is a spokesperson, Resolve. The charity aims to get fertility treatment better covered by insurance companies

Margolis posed for a second Playboy pictorial for the July 2008 issue. The pictorial was held in conjunction with a competition where the winner would accompany Margolis to a party at the Playboy mansion. A portion of the sales of her issue went to her charity, the Cindy Margolis Get a Download of This Fertility Fund.

In spring 2006, Margolis was winner of NBC's Celebrity Cooking Showdown. She teamed up with renowed celebrity chef Wolfgang Puck to win both the first round and the final round. In November of 2006, Margolis signed an exclusive poker representation agreement with Tropical Poker. Margolis has become a highly sought-after poker player and will represent Tropical Poker in the press, media interviews, poker events and appearances, as well as at the 2007 World Series of Poker.