Docetaxel in combination with prednisone is the standard of care in men with symptomatic castration-resistant prostate cancer (CRPC). However, a substantial proportion of men with CRPC do not benefit from docetaxel or other systemic therapy and those who do benefit invariably progress and die of (or with) prostate cancer. Resistance to chemotherapy in metastatic CRPC is a result of cellular mechanisms of drug resistance intrinsic to prostate cancer and general mechanisms common to different tumor types. Continued signaling from the androgen receptor, activation of oncogenic survival pathways by various receptor tyrosine kinases and crosstalk between the androgen receptor and these oncogenic survival pathways are hallmarks of progression of CRPC. General mechanisms of drug resistance include the existence of subpopulations of cancer cells with cellular mechanisms of resistance, resistance related to interactions between prostate cancer cells and their surrounding microenvironment and impaired drug delivery to the cancer cells. New therapeutics targeting these mechanisms are under evaluation in clinical trials. Drug resistance in metastatic CRPC is multifactorial and complex and development of new medical therapies remains challenging.