Metastatic prostate cancer has limited therapeutic options and has remained a major clinical challenge. Historically, prostate cancer has been widely recognized as a chemotherapy-resistant disease. However, clinical studies with anti-microtubule agents over the past decade have shown important efficacy in improving survival in patients with advanced disease. The favorable outcomes with microtubule-targeted agents have thus rekindled interest in such therapies for the clinical management of prostate cancer. Microtubules are dynamic polymers of tubulin molecules that play diverse roles within the cell. The dynamic property of microtubules is responsible for forming the bipolar mitotic apparatus, the mitotic spindle, that functions to precisely segregate the chromosomes during cell division. Thus, owing to the pivotal role that they play in the orchestration of mitotic events, microtubules provide excellent targets for anti-cancer therapy. Recent evidence also suggests that microtubules play a crucial role in the regulation of endocrine signaling pathways. Interestingly, microtubule-targeted agents such as taxanes not only inhibit cell division but also impair endocrine receptor signaling in prostate cancer. Herein, we provide an overview of the current status of microtubule-targeted therapies that are used in the treatment of prostate cancer and discuss novel mechanisms by which such therapies modulate endocrine signaling in prostate cancer. We also address the emerging roles of microtubule regulatory proteins in prostate carcinogenesis that could serve as attractive targets for prostate cancer therapy and might also serve as predictive biomarkers to identify patients who may benefit from endocrine and/or chemotherapy. This may have important implications in designing mechanism-based and targeted-therapeutic strategies for prostate cancer.