In spite of a growing body of knowledge of prescription drug misuse (PDM), several important gaps exist. This dissertation is comprised of three independent studies that advance knowledge of PDM among adolescents. Study 1 aims to provide a review of the epidemiology of adolescent PDM and offer a theoretical explanation of the problem using anthropological, cognitive-affective, and interpersonal theories of substance use. This theoretical discussion is important given that unlike illicit drugs, prescription drugs, when prescribed by health care professionals, are legal, pervasive, and often medically beneficial. The theories discussed in Study 1 highlight the unique qualities of PDM compared to use of illicit drugs. Study 2 aims to describe the prevalence and correlates of PDM and distinguish low- vs. high-frequency prescription drug misusers (PDMs) in a state population of youth in residential care for antisocial behavior (N = 723). This is the first known study to investigate the prevalence and correlates of PDM among youth in institutional care. Findings indicate that adolescents in residential care for antisocial behavior have high rates of PDM and comorbid psychiatric and behavioral problems. Youth served in institutional settings should be routinely screened and treated for PDM and co-occurring disorders. Study 3 used latent profile analysis (LPA) to identify subtypes of adolescent sedative/anxiolytic misusers (N = 247). LPA yielded three classes of sedative/anxiolytic misusers with significant heterogeneity across measures of psychiatric and behavioral problems. Class 1 (59.1%) was comprised of youth with significantly lower levels of currently distressing psychiatric symptoms, fewer lifetime traumatic experiences, less problematic substance use histories, less frequent antisocial behavior, and less impulsivity than youth in Classes 2 and 3. Class 2 (11.3%) youth had high levels of currently distressing psychiatric symptoms and more frequent antisocial behavior compared to youth in Classes 1 and 3. Class 3 (29.5%) youth evidenced levels of psychiatric and behavioral problems that were intermediate to those of Class 1 and 2 youth. Significant differences between classes were observed across a range of health, mental health, personality, and behavioral variables. Youth with comparatively high levels of anxiety and depression reported significantly more intensive sedative/anxiolytic misuse than their counterparts and may be at high risk for sedative/anxiolytic abuse and dependence.