This study examined a six-month prospective model of marijuana and alcohol problems among college students. Among marijuana users, there was an indirect positive association between use utility and Time 1 (T1) marijuana-related problems through T1 marijuana use, whereas there was a direct positive association between affect lability and T1 marijuana-related problems. A multi-group analysis of alcohol problems compared models for users of alcohol and marijuana and users of alcohol only. For both groups, there was a direct positive association between T1 use utility and T2 alcohol consumption and an indirect association with T2 alcohol problems via alcohol consumption. Impulsivity was directly and positively associated with T1 alcohol problems among the alcohol-only group. For the alcohol-only group, impulsivity moderated the association between T2 consumption and problems, making it stronger. Associations between affect lability and alcohol problems as well as alcohol consumption and problems were stronger in the alcohol and marijuana group. Results support differential pathways to substance-related problems, an indirect pathway, in which problems are an unintended consequence of goal-directed use activity, as well as direct and interactive pathways in which problems may be viewed as consequences of broader regulatory problems.