Prostate cancer is the second most common cancer among men. Despite advances in diagnosis and management, prostate cancer led to more than 300,000 deaths globally in 2020. Chemotherapy is a cornerstone of therapy for advanced prostate cancer and can prolong survival of patients with both castration-sensitive and castration-resistant disease. Herein, we present a comprehensive review of the data supporting implementation of chemotherapy in the modern treatment of advanced prostate cancer, with special attention to the use of chemotherapy for aggressive variant prostate cancer (e.g., neuroendocrine prostate cancer) and the combination of chemotherapy with androgen signaling inhibitors. As the field of prostate cancer research continues to rapidly evolve yielding novel agents and treatment modalities, chemotherapy continues to play an essential role in prolonging the survival of patients with advanced and metastatic prostate cancer.