As a playwright, May saw two of her plays ("A Matter of Position" and "Not Enough Rope") produced in 1962 and had her first crack at the director's chair, helming an Off-Broadway production of "The Third Ear" in 1964. She broke into film acting with incisive comic performances in Carl Reiner's "Enter Laughing" (based on his successful Broadway play) and Clive Donner's movie adaptation of Murray Schisgal's play "Luv" (both 1967), portraying Jose Ferrer's actress daughter in the former and Peter Falk's know-it-all wife in the latter. In 1969 May won accolades for directing a pairing of her play "Adaptation" and Terrence McNally's "Next" on the same Off-Broadway bill, the evening's success setting the stage for her movie debut as writer-director of "The New Leaf" (1971). A modern day screwball comedy, the film centered on a recently impoverished eccentric (Walter Matthau) who decides to marry (with murderous designs) a wealthy oddball botanist (May). Despite generally favorable notices, May had tried to stop the film's distribution claiming that Paramount (who had cut two of the movie's darkest scenes) was releasing a version of which she disapproved. She also wrote Otto Preminger's "Such Good Friends" that year, taking the pen name Esther Dale (oddly, the name of a well-known character actress) to protest the liberties Preminger had taken with her script.

May's experience as director of 1972's hilarious "The Heartbreak Kid" was a much better one. Scripted by Neil Simon, the film, which follows a Jewish New Yorker (Charles Grodin) as he meets and pursues the shiksa of his dreams (Cybill Shepherd) while honeymooning with his swarthy spouse, bore more than a passing resemblance to Nichols' "The Graduate" (1967). May won praise for her handling of potentially difficult material, and both Eddie Albert (as Shepherd's stern father) and daughter Jeannie Berlin (as the abandoned bride) earned Oscar nods. However, she was back in hot water with Paramount when she spent too much time editing her third feature "Mikey and Nicky" (1976), prompting the studio to seize it and release it in its still unfinished form. As in her previous films, betrayal--this time of Nicky by Mikey, his best and oldest friend--was at the heart of this offbeat study of petty gangsters. Though the film never quite overcame its stage origins (May had first written it as a play), superb performances by Falk, John Cassavetes, Ned Beatty as a hired killer, and Joyce Van Patten as Falk's estranged wife made it well worth watching, and the appearance of a properly edited print shown as part of "Buried Treasures" at the 1980 Toronto Festival of Festivals seemed to vindicate her original vision.

Warren Beatty asked May to work with him on the screenplay for a remake of 1941's "Here Comes Mr. Jordan", about a sports figure who dies before his time and is reincarnated. The result was "Heaven Can Wait" (1978), a charmingly whimsical mix of verbal and visual humor buoyed by strong performances from Beatty, Jack Warden, Grodin and Dyan Cannon. That same year, May also returned to screen acting, reteaming with Matthau for a segment of "California Suite", written by Simon. She reportedly did an uncredited polish on Sydney Pollock's "Tootsie" (1982), starring Dustin Hoffman, who would later star with Beatty and Isabelle Adjani in May's now-notorious "Ishtar" (1987). Considered by many critics as one of the worst film comedies ever made, "Ishtar" was in the tradition of the Bob Hope-Bing Crosby "Road to . . . " movies, with Beatty and Hoffman cast as untalented singer-songwriters caught up in international intrigue in North Africa. Like "Heaven's Gate" and "Waterworld", the production was the subject of numerous press stories which detailed shooting delays and the film's ever escalating budget due to cost overruns. Whether it was because May was a female helming a major studio picture or because there was some basis in fact to the stories can't really be determined. All the negative publicity, though, hurt "Ishtar" in its initial release--it has since found its champions--but the memory of its disastrous release may be enough to deny May further directorial assignments.

In 1980, May's return to stage acting reunited her with old pal Nichols, who starred as George opposite her Martha in a revival of Edward Albee's "Who's Afraid of Virginia Woolf?" at the Long Wharf Theater in New Haven, Connecticut. A decade and a half later, the duo worked together (with Nichols as producer-director and May as screenwriter) for the first time on a feature film, "The Birdcage" (1996), a remake of "La Cage aux folles" (1978), itself based on a French stage farce. May transposed the story of two aging homosexuals to Florida's South Beach and added a layer of political humor, still gearing it to the mass audience's stereotype of gay characters: the butch male and the feminine drag queen. The film enjoyed runaway box-office success, thanks to auspicious casting (Robin Williams, Nathan Lane, Gene Hackman, Dianne Wiest and Hank Azaria), Nichols' expert comic direction and her witty script. The pair teamed for "Primary Colors" (1998), a well-received, if over-long, political comedy-drama based on Joe Klein's 1996 novel about the first Clinton presidential campaign. May's shrewd adaptation, while lamenting the present course of American politics, also presented a strong argument why a flawed candidate can deserve your vote and earned her a second Best Adapted Screenplay Oscar nomination. May resumed her acting career appearing as in an hilarious supporting performance as Tracey Ullman's slightly dim cousin in Woody Allen's "Small Time Crooks" (2000).