The use of substances among youth experiencing homelessness is an important issue in the context of addressing the developing burden of morbidities arising due to illness, injury, physical and mental health concerns, and low rates of health care utilization among this population group. Youth experiencing homelessness report engaging in and being victimized by various forms of sexual behavior. Of interest in this systematic review were published studies investigating substance use in its association with perpetration of sexual offenses, engagement in sexual risk behavior, or experience of sexual victimization among homeless youth. A systematic search of 12 psychology, health, and social science electronic databases was conducted. Search terms included "homeless*," "youth," "sex crimes," "sexual victimization," "survival sex," "rape," "drugs," and "substance abuse." Twenty-three studies were identified that met the inclusion criteria. No studies statistically examining substance use in its association with perpetrating sexual offenses were located. Findings showed substance use was generally associated with sexual risk behavior or sexual victimization; however, it remains unclear whether substance use precedes or follows these behaviors and experiences. It is possible substances are used by homeless youth as a means of coping with sexual risk behavior and victimization. Implications of the review findings in relation to prevention and intervention approaches aimed to decrease the incidence and severity of health concerns among homeless youth are discussed.