OBJECTIVES: Survival is the predominant measure of metastatic castration-resistant prostate cancer (mCRPC) treatment benefit, but it does not account for the impact on how patients feel or function, which summarizes health-related quality of life (HRQoL). Contemporary mCRPC therapies have shown survival improvements and varying HRQoL impacts. In order to understand the true burden of illness (BOI) in these patients and how it is impacted by treatment, it is critical to understand how patient-centered outcomes are measured and interpreted. METHODS: This literature review identified MEDLINE publications reporting on HRQoL (including pain) in ≥50 mCRPC patients using predefined search terms: prostate, prostate cancer, castrate- or hormone-resistant, hormone refractory, androgen-independent, androgen independence and quality of life, HRQoL, pain, bone or cancer-related pain, fatigue, and weight loss.  RESULTS: Forty-four mCRPC studies were identified that met prespecified criteria and included 14 unique HRQoL instruments. Important HRQoL issues for mCRPC patients included pain, nausea/vomiting, and insomnia. The most commonly used measures were EORTC QLQ-C30, FACT-P, and the BPI/McGill pain questionnaires. Most of these instruments were not specifically developed for mCRPC patients and may not comprehensively capture symptoms important to this population. Further, identified studies did not use consistent definitions of clinically meaningful differences. Since 2010, using a variety of instruments in pivotal studies, 3 treatments (mitoxantrone, estramustine phosphate and docetaxel, and cabazitaxel) had no statistically significant impacts on HRQoL or pain, whereas 4 other treatments (abiraterone, enzalutamide, radium-223, and sipuleucel-T) reported statistically significant benefits for HRQoL or pain. CONCLUSIONS: HRQoL is an important complement to survival and other clinical endpoints to best understand treatment benefit in mCRPC. To give context to the relative impact of treatments on HRQoL, it is critical to understand the underlying BOI in this patient population and to standardize methods for measuring and quantifying the assessment of HRQoL in mCRPC.