Prostate cancer is the most common non-cutaneous cancer among men in the United States. Most will be diagnosed at an early stage, but a significant number will still develop metastatic castration resistant disease. Docetaxel has demonstrated improved quality of life and overall survival in metastatic castration-resistant prostate cancer but virtually all patients will ultimately become refractory to taxane therapy. Second-line options are limited and new effective chemotherapeutic agents or combinations are needed in this setting. This review will focus on cytotoxic compounds in clinical investigation either in combination with taxanes in the first or second-line setting and other novel compounds, such as platinums and microtubule-targeting agents that are in active clinical investigation.