The Handbook of Evidence-Based Mental Health Practice with Sexual and Gender Minorities represents the first compendium of evidence-based approaches to sexual and gender minority (SGM)-affirmative mental health practice. In the past several years, clinical researchers have begun developing and adapting evidence-based mental health treatment approaches to be affirmative of SGM individuals’ unique mental health. Because these approaches draw on research documenting unique psychosocial processes underlying SGM individuals’ mental health as well as adapt existing evidence-based treatments to impact these processes, these treatments can be considered evidence-based. Because these approaches promote effective coping with stigma-related stress and are often developed with feedback from SGM community members, these treatments can also be considered SGM-affirmative. This handbook compiles these approaches, including evidence-based treatments for specific populations within the SGM community (e.g., youth, transgender individuals, same-sex couples, parents, and bisexuals), for specific mental health problems (e.g., anxiety, depression, substance abuse, trauma, eating disorders, sexual health), and using novel modalities (e.g., group therapy; acceptance-based, dialectical behavior therapy; attachment-based, transdiagnostic therapy). Each chapter includes conceptual background and practical guidance so that mental health practitioners, researchers, educators, and students can both understand how to implement each of these approaches and develop future tests of their efficacy and the efficacy of other SGM-affirmative approaches.