With the surge in therapeutic options for men with castration-resistant prostate cancer (CRPC) comes increasingly complicated treatment decision making, highlighting the need for biomarkers that can identify appropriate patients for specific treatments and accurately assess disease response. Predictive biomarkers are factors related to the disease or the host that are associated with improvements in outcomes, such as survival, due to specific therapies. Such biomarkers have become of paramount importance in oncology to maximize the benefits of novel systemic agents while minimizing harm to individual patients and the costs to society. Given the number of newly approved and expensive systemic therapies, including novel hormonal therapies, chemotherapies, immunotherapies, and bone microenvironment-targeting therapies, predictive biomarkers are needed to give physicians a more rational sense of matching the right patient to the right therapy sequence at a given time. There are currently no validated predictive biomarkers in CRPC. We discuss potential predictive biomarkers in men with CRPC and how these may be developed in the context of therapeutic clinical trials.