Most men with metastatic prostate cancer respond to various types of androgen ablation but progress to castration-resistant disease. The TAX 327 and Southwest Oncology Group (SWOG) 99-16 clinical trials established docetaxel-based chemotherapy as preferred first-line treatment for most men with symptomatic metastatic castration-resistant prostate cancer (mCRPC). However, only about half receive benefit from docetaxel, and those who respond initially progress and eventually die of (or with) mCRPC. Both cellular mechanisms and the tumor microenvironment are implicated in the development of resistance to docetaxel. New agents are being evaluated for men with mCRPC, either as first-line treatment in combination with docetaxel, or in men progressing during or after treatment with docetaxel. Thus far, agents evaluated in phase III trials in combination with docetaxel have not improved outcome, including the vaccine GVAX, high-dose vitamin D (DN-101), and the antiangiogenic agent bevacizumab. In contrast, cabazitaxel, a taxane that is not cross-resistant to docetaxel, substantially improved the outcome of men progressing during or after treatment with docetaxel-based chemotherapy when compared with mitoxantrone and prednisone. However, translation of benefit of cabazitaxel demonstrated in the TROPIC (Treatment of Hormone-Refractory Metastatic Prostate Cancer) trial into general oncologic practice will be challenging because this agent may cause serious toxicity. With the approval of less toxic hormonal agents (eg, abiraterone acetate) in the setting of docetaxel-resistant mCRPC, clinicians will have an opportunity to balance benefits and harms of new agents in an individual patient and may be able to use different agents in sequence.