The role of chemotherapy in prostate cancer has evolved significantly over the past three decades. From the palliative gains offered by mitoxantrone to the survival improvements achieved with docetaxel and cabazitaxel, cytotoxic agents have become an indispensable part of the treatment arsenal, particularly in those with high volume metastatic disease and in castrate-resistant prostate cancer, despite the rise of novel agents such as androgen receptor pathway inhibitors (ARPIs). This chapter explores the development, mechanisms, indications, and toxicity profiles of the key chemotherapy agents used in prostate cancer management, namely docetaxel and cabazitaxel, while also reviewing less commonly used or historically trialled agents such as mitoxantrone, estramustine, epirubicin, and cyclophosphamide.