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Despite increased awareness of transgender lives and experiences, evidence suggests that transgender and gender nonconforming individuals continue to be exposed to pervasive invalidation and discrimination in the dominant culture. As such, culturally tailored treatment approaches are needed for meeting the mental health care needs of this marginalized population. Although recent theoretical and empirical advances have been made linking experiences of invalidation and discrimination to mental health disparities at a population level, conceptual models accounting for mental health consequences of invalidation at the individual level are lacking. As such, this article provides a detailed application of the Biosocial Model, the theoretical basis of dialectical behavior therapy (DBT), to the conceptualization and treatment of clinical distress in transgender individuals struggling to effectively cope with chronic invalidation of gender diversity. Application of DBT-informed case conceptualization and skills-training tailored to gender diverse people is provided with the goal of empowering clinicians with practical approaches for promoting the psychological health and flourishing of transgender and gender-nonconforming patients.