With equal skill, he has since played both romantic leads and supporting character roles ranging from the nerdy to the nasty and gave a memorable performance as the hero's scheming secretary in Warren Beatty's "Heaven Can Wait" (1978). As a jewel-thief besmitten with Miss Piggy in "The Great Muppet Caper" (1981), Grodin stole the film by playing the romance "straight" with apparent hilarious sincerity. One of his finest tongue-in-cheek performances is as the priggish and irritating embezzler handcuffed throughout most of the film to Robert De Niro in the odd-couple comedy, "Midnight Run" (1988). Grodin continues to alternate between stage and film and in 1985 he wrote, produced and starred in a satire of Hollywood filmmaking, "Movers and Shakers".

Grodin continued to be a regular presence in Hollywood films of the 90s. He starred with James Belushi in an engaging switched identity comedy, "Taking Care of Business" (1990), co-starred with an irrepressible canine in the surprise hit, "Beethoven" (1992) and played a supporting role as the accountant friend of "Dave" (1993), who balances the federal budget in a marathon overnight session for his good friend Kevin Kline, the imposter president of the USA.

In January 1995, Grodin began hosting an eponymous talk show on the CNBC cable network which was canceled in June 1998 in part because of declining ratings and also because of Grodin's nightly diatribes agains social ills and injustices. He has also written three books including a 1989 autobiography, "It Would Be So Nice If You Weren't Here", and its 1994 follow-up, "We're Ready for You, Mr. Grodin".