PURPOSE/OBJECTIVES: To evaluate the effectiveness of exercise interventions on overall health-related quality of life (HRQOL) and its domains among adults scheduled to, or actively undergoing, cancer treatment. DATA SOURCES: 11 electronic databases were searched through November 2011. In addition, the authors searched PubMed's related article feature, trial registries, and reference lists of included trials and related reviews. DATA SYNTHESIS: 56 trials with 4,826 participants met the inclusion criteria. At 12 weeks, people exposed to exercise interventions had greater improvement in overall HRQOL, physical functioning, role functioning, social functioning, and fatigue. Improvement in HRQOL was associated with moderate-to-vigorous intensity exercise interventions. CONCLUSIONS: Exercise can be a useful tool for managing HRQOL and HRQOL domains for people scheduled to, or actively undergoing, cancer treatment. More methodologically rigorous trials are needed to examine the attributes of exercise programs most effective for improving HRQOL. IMPLICATIONS FOR NURSING: Evidence from this review supports the incorporation of exercise programs of moderate-to-vigorous intensity for the management of HRQOL among people scheduled to, or actively undergoing, cancer treatment into clinical guidelines through the Oncology Nursing Society's Putting Evidence Into Practice resources.