Castration-resistant prostate cancer (CRPC) is associated with multiple symptoms that have a significant impact on patients’ health-related quality of life (HRQoL). We were interested to establish the extent to which disease and treatment-related symptoms affect the HRQoL of patients with CRPC from the patients’ perspective, so we undertook a review of current literature and also obtained feedback at an international meeting. Our review of evidence from the literature found that the majority of patients with CRPC are significantly affected by a number of disease- and treatment-related symptoms that have a negative impact on their HRQoL. These findings highlighted the need for treatment decisions to be based on an assessment of quality as well as quantity of life for this patient population. We also established that there are substantial differences in the perception of HRQoL between patients and their physicians. Physicians remain the most direct influence on patient choice, therefore they have a responsibility to fully inform patients about their disease stage, the available treatment options and potential impact on HRQoL. Despite advances in the treatment and management of CRPC, further improvements in HRQoL are necessary. As a consequence, all future treatment approaches for CRPC should take into account both survival benefit and the impact on HRQoL. Furthermore, patients, their partners and physicians should all be involved in the treatment decision-making process. This should include an assessment of HRQoL to ensure potential impact and benefit is fully understood.