Shortbus centres on two characters in long-term relationships, both of whom want to open up their marriages sexually, albeit for different reasons.

One is Sofia, a relationship counsellor who has never had an orgasm. She's been faking it for years with her husband Rob. The film opens as Sofia sets out on a far-flung quest for her own personal consummation.

The other central character is James, who comes to Sofia as a client with his long-term boyfriend Jamie to discuss a recent development in their relationship. James has suggested that they open up their sexual relationship to other partners, and the adoring Jamie is reluctant but willing to give it a try. Actually, James is secretly trying to prepare his lover for his own imminent suicide. James is working hard on a mysterious video which, we eventually discover, is meant as a farewell note.

Three important characters orbit these two couples. Severin is a dominatrix prostitute/artist who lives in a tiny industrial storage unit. Her artistic work involves taking Polaroid photos of strangers captured at their most vulnerable. She has never had a deep lasting relationship with anyone, and loneliness is taking its toll. She offers to help Sofia find her orgasm. In return, Sofia will give Severin free therapy to help her in her quest for a meaningful relationship. They trade their services in the confined but cosy setting of a sensory deprivation tank (where customers float in a pitch-black, soundproof saltwater-filled tank).

Meanwhile, a former model/now singer named Ceth falls for James and Jamie – not separately, but as a couple. He pursues the idea of a 'monogamous' three-way relationship with them. We also meet James’ stalker, Caleb, who’s living in an apartment with a grandstand view of James and Jamie's apartment. He observes James obsessively and is shocked by the arrival of Ceth, seeing him as a danger to James and Jamie's 'perfect' relationship. He sets out to eliminate that threat.

All the characters converge on Shortbus, a modern-day weekly salon in the Parisian Gertrude Stein tradition. (The name 'Shortbus' refers to the classic American yellow public school bus. Most "normal" children travel in the long yellow bus. The short bus is reserved for disabled, emotionally-disturbed or gifted children, anyone with "special needs".)

The salon takes place in the D.U.M.B.O. (Down Underneath the Manhattan Bridge Overpass) area of Brooklyn in the multi-room loft/domicile of host Justin Bond, who has carefully fostered a communitarian nexus of art, music, politics and polysexual public sex at his weekly gathering. Justin sees Shortbus as sanctuary of the old New York spirit, circling its wagons against a rising conservative national tide and a rapidly gentrifying city. He remains enthusiastic about the city’s unique character and talks about it as a "motherboard" – dominated by its circuitry of desire for connection through sex, love and creation. He warns that the city’s emotional infrastructure is old and outdated and it may not be able to handle the ever-multiplying hopes and dreams of its inhabitants.

Indeed, his metaphor achieves naturalistic manifestation in the film’s closing scenes which take place during a city-wide blackout. By then, all of the characters have experienced massive life changes. James' suicide attempt is foiled by his stalker Caleb, and his relationship with Jamie is put on a new footing. Severin, Rob and Ceth begin to free themselves from their own personal prisons. And Sofia finds her orgasm. When she does, all the lights come back on.

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