Over 1.2 million Americans aged 13 years and older have been diagnosed with human immunodeficiency virus (HIV). While HIV incidence has been declining since 2017, the risk of HIV acquisition and transmission persists among persons who use drugs via injection drug use and unprotected sexual intercourse associated with substance use. Untreated substance use disorder (SUD) is associated with poor adherence to HIV antiretroviral therapy, poor HIV outcomes, and increased risk for HIV acquisition. Herein, we describe the intertwined syndemic of HIV and SUD, as well as treatment strategies and evidence-based public health efforts to engage and retain persons who use drugs into care.