Persons whose experienced or expressed gender differs from their sex assigned at birth may identify as transgender. Transgender and gender-diverse persons may have gender dysphoria (i.e., distress related to this incongruence) and often face substantial health care disparities and barriers to care. Gender identity is distinct from sexual orientation, sex development, and external gender expression. Each construct is culturally variable and exists along continuums rather than as dichotomous entities. Training staff in culturally sensitive terminology and transgender topics (e.g., use of chosen name and pronouns), creating welcoming and affirming clinical environments, and assessing personal biases may facilitate improved patient interactions. Depending on their comfort level and the availability of local subspecialty support, primary care clinicians may evaluate gender dysphoria and manage applicable hormone therapy, or monitor well-being and provide primary care and referrals. The history and physical examination should be sensitive and tailored to the reason for each visit. Clinicians should identify and treat mental health conditions but avoid the assumption that such conditions are related to gender identity. Preventive services should be based on the patient's current anatomy, medication use, and behaviors. Gender-affirming hormone therapy, which involves the use of an estrogen and antiandrogen, or of testosterone, is generally safe but partially irreversible. Specialized referral-based surgical services may improve outcomes in select patients. Adolescents experiencing puberty should be evaluated for reversible puberty suppression, which may make future affirmation easier and safer. Aspects of affirming care should not be delayed until gender stability is ensured. Multidisciplinary care may be optimal but is not universally available.