Gender variance is an umbrella term used to describe gender identity, expression, or behavior that falls outside of culturally defined norms associated with a specific gender. In recent years, growing media coverage has heightened public awareness about gender variance in childhood and adolescence, and an increasing number of referrals to clinics specializing in care for gender-variant youth have been reported in the United States. Gender-variant expression, behavior, and identity may present in childhood and adolescence in a number of ways, and youth with gender variance have unique health needs. For those experiencing gender dysphoria, or distress encountered by the discordance between biological sex and gender identity, puberty is often an exceptionally challenging time. Pediatric primary care providers may be families' first resource for education and support, and they play a critical role in supporting the health of youth with gender variance by screening for psychosocial problems and health risks, referring for gender-specific mental health and medical care, and providing ongoing advocacy and support.