To explore the social context of drug use and sexual behaviours that put male-to-female (MTF) transgenders at risk for HIV, focus groups were conducted consisting of African American, Latina and Asian and Pacific Islander MTF transgenders (N = 48) who reside or work in San Francisco, California. Participants were likely to report having unprotected sex with primary partners to signify love and emotional connection, as well as to receive gender validation from their partners. In contrast, viewing sex work with customers as a business encouraged intentious to use condoms. Safer sex intentions with customers were frequently undermined by urgent financial needs, which stemmed from transphobia, employment discrimination and costly procedures associated with gender transition. Participants reported using drugs as a way to cope with or escape life stresses associated with relationships, sex work, transphobia and financial hardship. Interventions with at-risk MTF transgenders should address the interpersonal and social context of unsafe sex and drug use, particularly the unique roles of relationship issues with male partners, stigma, discrimination and community norms regarding sex work and drug use.