Approximately 15% of patients with prostate cancer are diagnosed with high-risk disease. However, the current definitions of high-risk prostate cancer include a heterogeneous group of patients with a range of prognoses. Some have the potential to progress to a lethal phenotype that can be fatal, while others can be cured with treatment of the primary tumour alone. The optimal management of this patient subgroup is evolving. A refined classification scheme is needed to enable the early and accurate identification of high-risk disease so that more-effective treatment paradigms can be developed. We discuss several principles established from clinical trials, and highlight other questions that remain unanswered. This Review critically evaluates the existing literature focused on defining the high-risk population, the management of patients with high-risk prostate cancer, and future directions to optimize care.