Objectives: Substance use among young adult childhood cancer survivors (YACCSs) has been found to increase during survivorship, resulting in increased risk of developing long-term negative health outcomes. This investigation sought to determine various risk and protective factors of tobacco, alcohol, or marijuana use over time among a sample of YACCSs. Methods: 127 YACCSs (57% Hispanic, 55% female, average age at diagnosis 12.4 years) who were diagnosed with any cancer type (except Hodgkin lymphoma) at two large pediatric medical centers in Los Angeles County between 2000 and 2007 responded to two surveys separated by ∼5 years. Bivariate logistic regression models were used to assess independent clinical and psychosocial Time 1 variables associated with each substance use outcome at Time 2. Time 1 variables significant at p < .10 were included in multivariable logistic regression models for each Time 2 substance use variable. Results: Rates of 30-day use increased over time for binge drinking alcohol (from 25.6% to 37.7%), marijuana (from 10.6% to 22.1%), and cigarette/tobacco (from 8.9% to 12.2%). Of the following Time 1 variables, marijuana use, cigarette use, and binge drinking were associated with Time 2 marijuana, cigarette, and binge drinking, respectively. Of the following clinical factors, receipt of more intensive cancer treatment was associated with decreased tobacco use. All other psychosocial and clinical factors analyzed were not associated with any increase or decrease in substance use. Conclusions: A greater emphasis on early health education efforts regarding the health risks of tobacco, alcohol, and marijuana use is needed in this at-risk population.