Background: Relative to youth in regular high schools, alternative high school (AHS) youth are at high risk for alcohol, tobacco, and other drug (ATOD) misuse. Prevention and cessation efforts are needed for this population. Methods: A systematic, exhaustive literature search was completed to identify ATOD misuse prevention and cessation research studies with AHS youth. Results: For the AHS population, 23 ATOD misuse prevention or cessation program evaluations were located. This review indicated that successful efforts have focused on instruction in motivation enhancement, life coping skills, and decision making. Conclusions: Alcohol, tobacco, and other drug misuse prevention and cessation programming for AHSs is effective, delivered in the classroom or as a school-based clinic. There is little evidence, though, that this programming is effective when delivered through other modalities such as via computer or bridging beyond the school setting. More research and application of evidence-based programming are recommended for youth in AHS settings.