Abstract Introduction Research indicates a link between adolescent e-cigarette use and combustible tobacco cigarette (CTC) initiation, and recent studies suggest their connection with marijuana uptake. Our 3-year longitudinal cohort study investigated the implications of adolescent, peer, and family e-cigarette use with adolescents’ expectations and willingness to initiate CTC use, and subsequent CTC and marijuana use. Aims and Methods Relationships were examined in a secondary analysis of a 3-year longitudinal cohort subsample involving adolescents enrolled in alternative California high schools (N = 1025). Analyses examined responses over three yearly observations. Family, peer, and respondents’ e-cigarette use, respondents’ positive cigarette expectancies and willingness to use CTCs were assessed in the study’s first year (T1). CTC use in the survey’s second year (T2) and marijuana use in the third year (T3) were assessed via path analysis. Results Respondents reporting at least one family member or peer using e-cigarettes were more likely to use e-cigarettes at T1 than those whose peers/family members did not. They reported more positive expectancies about CTCs and greater willingness to initiate use. These variables predicted CTC use at T2, which directly anticipated marijuana use in the survey’s third year (T3), as did adolescents’ use of e-cigarettes at T1. All model relations were statistically significant. Conclusions Analysis demonstrated the strong association of family members’ and peers’ behaviors with adolescent e-cigarette use, and the temporal precedence of e-cigarette use with subsequent CTC and marijuana uptake. The predictive implications of e-cigarettes for other dangerous substance use should be examined in future prevention campaigns. Implications The presented study expands upon existing literature connecting adolescent e-cigarette use and later CTC and marijuana use. The findings indicate the significant implications of exposure to e-cigarette use by parents and peers and demonstrate in a longitudinal 4-year panel survey the direct and indirect predictive implications of e-cigarette use for CTC and marijuana uptake. The research illustrates the utility of programs and campaigns that target peer and family groups to maximize impacts on adolescent willingness to try CTCs, positive expectancies, and possible onset of CTC and marijuana use.