This paper reviews the most recent literature describing the bio-psycho-social challenges that may be faced by adolescent males who have sex with males (AMSM) and outlines recommendations for screening, medical and psychosocial concerns, and prevention for this population. Emerging research has demonstrated that adverse childhood experiences (ACEs) disproportionately affect AMSM, which can impact lifelong psychosocial functioning. In addition, significant medical advances in HIV prevention should be incorporated into primary care for adolescents and young adults at risk for HIV. Pediatricians need to understand the psychological and physical health risks which may be unique to AMSM. Screening and referral for depression, anxiety, substance use, and/or high-risk sexual behavior is especially important for this sub-group of adolescents and young adults. For sexually active AMSM, HIV and STI screening (including screening of extragenital sites) should be performed regularly, and providers should encourage the use of pre-exposure prophylaxis for patients at risk for HIV.