While many Indigenous languages have terms for individuals who combine masculinity with femininity in some way, Indigenous gender minority people have increasingly come to self-identify using the pan-Indigenous term “two-spirit.” This chapter examines key factors shaping the mental wellness of two-spirit people, such as the negative impact of residential and boarding school incarceration, and highlights available data on anxiety, depression, posttraumatic stress disorder, suicidality, and substance use. Reducing the mental health disparities that two-spirit people face is made more challenging by the lack of culturally informed and supportive health services. The authors describe factors that may buffer the minority stressors that lead to negative mental health outcomes and may increase wellness. The chapter concludes with a discussion of promising directions for future research.