According to Desmond Child, Steven Tyler came up with the idea after mistaking Mötley Crüe singer Vince Neil for a woman with long blonde hair.

[8] In his book The Heroin Diaries, Mötley Crüe's Nikki Sixx concurs that the song was inspired by Neil.

– Steven Tyler[9] Of "Cruisin' for the ladies", Child said, "I don't think Van Halen would put that on the B-side of their worst record.

[13]Despite the song's mainstream success, "Dude (Looks Like a Lady)" has been accused of being transphobic, with "its lyrics and music video’s offensive insinuations about trans women.

"[14] In 2019, Child confirmed that the song was about a man who "just walks into a bar and sees this gorgeous blonde up on the stage and then goes backstage after the show and then she 'whips out a gun, tries to blow me away.

'"[10] Child has refuted all allegations of transphobia, describing the song as "accepting" because of the lyric, "Never judge a book by its cover, or who you're going to love by your lover.

[15] After Caitlyn Jenner called "Dude (Looks Like a Lady)" her "theme song" in 2017, backlash ensued from fans and from LGBT activists due to the perceived transphobia.

Joe Perry's wife Billie also appears in the music video, pretending to play the saxophone on stage.

There are also some provocative sexual performances, both led by singer Steven Tyler as well as a presumed female who has her skirt torn off to reveal the Aerosmith "wings" tattoo on her buttocks.

The song has long been a staple on both rock radio and in concert, as the band has regularly rotated it into their set lists over the years.

Concurrent with its chart run, the song was played in the 1987 comedy film Like Father Like Son, starring Kirk Cameron and Dudley Moore.

Professional wrestler Roddy Piper appeared as a guest VJ on MTV shortly after the song's release.

Randi Mayem Singer, the writer of Mrs. Doubtfire, credits "Dude (Looks Like a Lady)" as one of the most important songs ever written and as the direct influence for writing the script.

[25][26] The song was also featured in the movie It's Pat where the title character (played by Julia Sweeney) sings a karaoke version at their wedding reception.

Colombian singer-songwriter Shakira sang the song with Steven Tyler on MTV Icon and also included it on the set list of her Tour of the Mongoose.