Health-related quality of life (HRQL) is a multidimensional subcomponent of quality of life involving subjective appraisal of various dimensions of one’s life that can be affected by health or health-related interventions. There is considerable evidence demonstrating that exercise consistently results in meaningful improvements in an array of HRQL outcomes. Advances in the conceptualization of HRQL and recent evidence identifying select moderators and mediators of the effects of upon HRQL outcomes have important implications for the design and delivery of exercise interventions. Taken collectively, contemporary findings support the utility of adopting a hierarchical, bottom-up approach to the investigation of the effects of exercise upon HRQL.