Positive youth development interventions are strategies to address adolescent health risk behaviors and are recommended in Healthy People 2020. Although the incorporation of spirituality into these programs has been recommended, much of the empirical literature actually addresses religiosity rather than spirituality. The purpose of our review of 36 studies published between 2007 and 2013 was to (1) examine the relationship of religiosity and/or spirituality to substance use and abuse in adolescence, (2) discuss the measurement and meaning of the concept of spirituality in contrast to religiosity in adolescence, and (3) discuss the implications of these empirical studies for the concept of positive youth development. Findings from this literature review supported earlier findings of an inverse relationship between religiosity and substance use, a lack of or inconsistent definition of spirituality and religiosity as well as limited measures to address these constructs. Recommendations from this review include dedicated work by interdisciplinary teams to address consistency in definitions and creation of consistent tools that include consideration of the stages of development included in the adolescent years. From a research and clinical perspective, an interprofessional approach to clarify the concepts of spirituality and spiritual development would not only benefit research but could inform the substance abuse prevention field. This work is essential to insure that evidence-based strategies, which include religiosity and spirituality, are developed with the goal of protecting youth and supporting positive development of adolescents.