Molko was born in Brussels, Belgium to an American father of Italian heritage and a British mother of Scottish Catholic descent. He has an older brother named Stuart. Molko's family moved frequently during his childhood; the family lived in Dundee, Liberia, Lebanon and Belgium, where they eventually settled in the village of Longeau near the border with Luxembourg, where Molko attended the American International School of Luxembourg (AISL).
Although Molko was brought up in a strict household that disapproved of artistic expression (his father wanted him to become a banker), he rebelled by assuming an androgynous image, wearing nail polish, lipstick, and eyeliner, and listening to punk music. He initially attended the European School of Luxembourg (ESL), but left due to excessive bullying. He attended the American International School of Luxembourg (AISL) before studying drama at Goldsmiths College in London.
Although Molko and Placebo co-founder Stefan Olsdal had both attended the American International School of Luxembourg (AISL), they had not been friends. When Molko was living in London, he ran into Olsdal at South Kensington tube station and invited him to one of his gigs he played with Steve Hewitt in a group called Ashtray Heart.
Along with Hewitt and Olsdal, Molko had a role in the 1998 film Velvet Goldmine, for which Placebo performed the T. Rex song "20th Century Boy". He played Malcolm, a singer of the fictional glam rock band, "The Flaming Creatures", who resembled the early Alice Cooper band.
During Placebo's live performances Molko has played a number of instruments, including guitar, bass guitar, keyboards, harmonica and saxophone.
Molko is openly bisexual. He has a son, who was born in 2005.
In December 2012 Molko received an Honorary Fellowship from Goldsmiths College, University of London.
He has performed, as a guest vocalist and with other artists on Placebo's records, on tracks by:The Cure – "If Only Tonight We Could Sleep" (live)
Justin Warfield – "Spite & Malice"
Losers – "Summertime Rolls"
Asia Argento – "Je T'aime, Moi Non Plus" (Serge Gainsbourg and Jane Birkin cover)
Alison Mosshart from The Kills – "Meds"
Michael Stipe of R.E.M. – "Broken Promise"
Faultline & Françoise Hardy – "Requiem for a Jerk" (Serge Gainsbourg cover)
Timo Maas – "Pictures", "Like Siamese", "First Day", "College 84"
Kristeen Young – "No Other God" on X
Dream City Film Club – "Some", "Billy Chic"
Jane Birkin – "Smile"
T. Rex – "20th Century Boy" (live cover, feat. David Bowie), "Without You I'm Nothing"
AC Acoustics – "Crush"
Alpinestars – "Carbon Kid"
Trash Palace – "The Metric System"
Hotel Persona – "Modern Kids"
Indochine – "Pink Water 3"
Prova Symphonica conducted by Michel Bisceglia – "Across the Universe" (The Beatles cover), "Ne me quitte pas" (Jacques Brel cover, both live)
Westbam – "Sick"
Fiona Brice – "West End Girls" (Pet Shop Boys cover)
Trash Palace – "Can't Get You Out of My Head" (Kylie Minogue cover, live)
Molko wrote the English lyrics to "Pink Water 3", a song by Indochine from the album Alice & June, released in 2005.
Molko was friendly with David Bowie; Bowie sang on Placebo's "Without You I'm Nothing" and on the "20th Century Boy" cover live.
Molko uses a variety of guitars. In the Sleeping With Ghosts era, he used Gibson SGs ("The Bitter End", "Every You Every Me", "Plasticine", "Black-Eyed", "Without You I'm Nothing", "Special K", "Bulletproof Cupid", "Soulmates/Sleeping With Ghosts", "Special Needs", "This Picture"), Fender Jaguars ("Allergic", "Nancy Boy", "Bionic", "Centrefolds"), a Fender Thinline Telecaster ("Taste in Men"), a Fender Jazzmaster ("Pure Morning"), and a Fender Bass VI ("Slave to the Wage"). For amplification he used a Marshall 6100LM.
Through the Meds tour, he used Gretsch Duo Jets ("Infra-Red", "Because I Want You", "Song to Say Goodbye", "One of a Kind", "The Bitter End", "Running Up that Hill", "Special K"), Gibson SGs ("Special Needs", "Every You Every Me", "Black-Eyed", "Without You I'm Nothing"), a Fender Jaguar ("Drag", "Nancy Boy", "I Know"), a Fender Thinline Telecaster ("Twenty Years", "Taste in Men"), and a Gibson Chet Atkins SST ("Meds"). His amplifier was a Fender Twin Reverb.
In the Battle for the Sun tour, he still used Gretsch Duo Jets ("Devil in the Details", "Come Undone", "Follow The Cops Back Home"), a Gibson SG ("Bright Lights"), Fender Cyclone ("Ashtray Heart", "The Never-Ending Why", "Breathe Underwater", "Teenage Angst"), a Gibson Les Paul ("For What It's Worth", "Speak in Tongues", "Julien", "Meds"), a Fender Telecaster Thinline ("Kitty Litter"), and a Fender Toronado ("Battle for the Sun"). His pedalboard consisted of a Boss TU-2 chromatic tuner, Electro Harmonix Holy Grail reverb, MXR Phase 90 phaser, two Electro Harmonix Hot Tubes distortion units, Boss DD-3 delay, MXR Distortion + booster, MG Monovibe chorus/vibrato, Electro Harmonix No. 1 Echo delay and a Radial Loopbone effect chain switcher.
In 2010, he signed an endorsement contract to use Orange amps.Velvet Goldmine (1998) – Malcolm of The Flaming Creatures
Sue's Last Ride (2001) – executive producer