While research on homeless adolescents and young adults evidencing substance use disorder is increasing, there is a dearth of information regarding effective interventions, and more research is needed to guide those who serve this population. The current study builds upon prior research showing promising findings of the community reinforcement approach (CRA) (Slesnick, Prestopnik, Meyers, & Glassman, 2007). Homeless adolescents and young adults between the ages of 14 to 20 years were randomized to one of three theoretically distinct interventions: (1) CRA (n = 93), (2) motivational enhancement therapy (MET, n = 86), or (3) case management (CM, n = 91). The relative effectiveness of these interventions was evaluated at 3, 6, and 12 months post-baseline. Findings indicated that substance use and associated problems were significantly reduced in all three interventions across time. Several moderating effects were found, especially for sex and history of childhood abuse. Findings show little evidence of superiority or inferiority of the three interventions and suggest that drop-in centers have choices for addressing the range of problems that these adolescents and young adults face.