Drug development for castration resistant prostate cancer (CRPC) is challenging, since this cancer is still associated with high mortality and limited therapeutic options. In 2004, docetaxel became the first-line chemotherapy for CRPC improving survival by a few months and remains the standard of care in CRPC patients. However, existing or developing resistance to docetaxel in patients is the main limitation of its efficacy. The present review presents the molecular mechanisms involved in docetaxel toxicity and in docetaxel resistance in prostate cancer cells. We outlined the endogenous mechanisms of resistance and the role of tumor microenvironment in the resistance of CRPC to docetaxel. This has led us to focus on molecules associated with resistance, such as the molecular chaperones heat shock proteins (HSPs) and clusterin (CLU), and the cytokines interleukin-6 (IL-6) and the divergent member of the tumor growth factor family MIC-1 (macrophage inhibitory cytokine-1 also named GDF-15). We discuss their interest as blood-based markers to monitor docetaxel resistance. Finally, new therapies intended to overcome docetaxel resistance of CRPC targeted on these molecular resistance pathways are present.