Transgender (or trans) is an umbrella term for individuals who experience their gender differently from what is associated with the sex they were assigned at birth. Individuals who are nonbinary experience their gender outside binary conceptions of gender. Although research has predominantly focused on negative mental health outcomes for transgender and non-binary (TNB) individuals, an emergent literature has begun to explore protective and health-promoting factors and dimensions of psychological well-being. In this Review, we discuss the sociocultural context for TNB people, beginning with a brief history of TNB identity before highlighting frameworks for understanding the higher prevalence of certain mental health concerns among TNB individuals. Next, we summarize the predictive factors associated with higher rates of depression, anxiety, suicidality, trauma-related concerns, disordered eating behaviours and substance use. We also review TNB coping, resilience and resistance to anti-trans stigma, as well as psychological well-being, flourishing and gender euphoria. Tying these topics together, we discuss affirming interventions for reducing mental health disparities and promoting psychological health in TNB individuals and communities. We conclude by discussing future research directions.