Shifting drug use patterns away from traditional illicit drugs (i.e., heroin, cocaine, methamphetamines) and toward prescription drug misuse among adolescents necessitates a renewed theoretical emphasis in adolescent drug use research. Given the unique processes and perspectives associated with prescription drug misuse, theoretical connections to prescription drug misuse likely show different patterns than prior research has shown with marijuana and other illicit drugs. Using data from the 2009 National Survey on Drug Use and Health, the authors apply concepts of social control theory, social learning theory, and strain theory to prescription drug misuse and draw comparisons with the predictors of marijuana and other drug use. Findings indicate that social learning, social control, and strain measures exert unique and independent influences on all three categories of adolescent substance use. Despite the similar theoretical effects across categories of substance use, many notable differences in theoretical processes are evident, especially for prescription drug misuse.