He came to prominence in the late 1970s as co-founder, lead vocalist and keyboardist of the new wave band Devo, whose "Whip It" was a top 20 single in the US in 1980, peaking at No.

In addition to his work with Devo, Mothersbaugh has made music for television series, films and video games via his production company, Mutato Muzika.

He grew up with two younger brothers, Bob and Jim, who are both musicians, and two sisters, Amy and Susan, and graduated from Woodridge High School in Peninsula, Ohio.

Mothersbaugh attended Kent State University as an art student, where he met Devo co-founders Gerald Casale and Bob Lewis.

[8] Intrigued by the concept, Mothersbaugh joined them, building upon it with elements of early post-structuralist ideas and oddball arcana, most notably unearthing the infamous Jocko-Homo Heavenbound pamphlet[9] (the basis for the song "Jocko Homo").

Their first project was a soundtrack for the flop horror film Slaughterhouse Rock, starring Toni Basil and they released the studio albums Total Devo (1988) and Smooth Noodle Maps (1990), on Enigma.

The award aims to celebrate "pioneering artists whose genre-defying work exemplifies the bold, innovative spirit of Bob Moog".

[15] Devo was scheduled to perform at Moogfest, but canceled three days beforehand after Mark's brother Bob Mothersbaugh (lead guitar) injured his hand.

He and Gerald Casale collaborated with Austin, Texas, band the Octopus Project to perform "Girl U Want" and "Beautiful World" at the event instead.

[16] In 1989, Mothersbaugh and other members of Devo were involved in the project Visiting Kids, releasing a self-titled extended play (EP) on the New Rose label in 1990.

[20][21] His music has been a staple of the children's television shows Rugrats, Beakman's World, Santo Bugito and Clifford the Big Red Dog.

This work is often performed with Mutato Muzika, the music production company he formed with several other former members of Devo including his brother, Bob Mothersbaugh.

As a prelude to the Myopia exhibit opening in Cincinnati, Ohio, Mothersbaugh held a concert gathering which included Devo songs and movie scores played in a classical style, an address to the audience with anecdotes, and musical pieces he specifically composed for a six-keyboard hybrid originally used for teaching lessons, that was refurbished by his brother Bob and contained a counter in the center for keeping time.

He favored a set of stainless steel frames for regular use made by a Los Angeles shop called LA Eyeworks and says he purchased as many pairs as he could find because they tended to break or get stolen by fans.

[34][35] In a joint venture with eyewear manufacturer Shane Baum, Mothersbaugh has designed his own branded frames for sale, made of beryllium with a stainless steel chrome finish, in three different styles as of 2015.

The Baumvision press release states that the unisex model "Francesca" is named for one of Mothersbaugh's pug dogs which is a simultaneous hermaphrodite that is also called Frank.

In August 2020, Mothersbaugh recounted that he "nearly died" of the disease, and was in a delusional state while infected; he came to believe that he had been hospitalized after being hit by a brick in Little Tokyo, and repeatedly urged his family members to search for his attackers.