Objectives: We assessed the association between minority stress, mental health, and potential ameliorating factors in a large, community-based, geographically diverse sample of the US transgender population. Methods: In 2003, we recruited through the Internet a sample of 1093 maleto-female and female-to-male transgender persons, stratified by gender. Participants completed an online survey that included standardized measures of mental health. Guided by the minority stress model, we evaluated associations between stigma and mental health and tested whether indicators of resilience (family support, peer support, identity pride) moderated these associations. Results: Respondents had a high prevalence of clinical depression (44.1%), anxiety (33.2%), and somatization (27.5%). Social stigma was positively associated with psychological distress. Peer support (from other transgender people) moderated this relationship. We found few differences by gender identity. Conclusions: Our findings support the minority stress model. Prevention needs to confront social structures, norms, and attitudes that produce minority stress for gender-variant people; enhance peer support; and improve access to mental health and social services that affirm transgender identity and promote resilience.