Challenges in the discovery of more potent agents to treat the castration-resistant prostate carcinoma (CRPC) reflect the frustrating condition due to development of its drug-resistance in addition to hormone-refractoriness. Although among the different CRPC therapy modalities, the chemotherapy regimens might seem conceptually outclassed as exhibiting a scant tumor cell-selectivity if compared with new molecular mechanism-based agents (so-called "smart drugs"), nevertheless, combo-therapies which combine the chemotherapeutic highly killing potential with specific mechanism-targeting products, seem to be effective antitumor measures. Thus, both microtubule (taxanes, epothilones, noscapine, Vinca-derivatives) and actin filament (pertenotoxins, cytochalasin D)-targeting agents may supply valuable outcomes in CRPC, either alone or in combination with "smart drugs" such as tyrosine- or multi-kinase receptor blockers, mTOR (mammalian target of rapamicin) inhibitors, monoclonal antibodies against various growth factor signaling receptors. Among the microtubule-inhibiting drugs, taxanes are able, by binding the tubulin, to cause polymerization and stabilization of the microtubules with following suppression of their dynamic properties at the mitotic spindle, that results in cancer cell cycle block at G2/M phase together with apoptosis. Cabazitaxel, a novel taxane-based agent, unlike other taxane compounds, exhibits low propensity for P-glycoprotein (Pgp)-mediated plasmalemmal drug efflux pump, thus, avoiding the development of taxane-resistance. Epothylones are a family of novel microtubule-targeting drugs, like taxane inhibiting microtubule dynamic behaviour at mitotic spindle and, therefore, preventing cancer cells from mitosis. Unlike docetaxel and paclitaxel, epothilones maintain their cytotoxic performance even in cancer overexpressing Pgp. Epothilone B-promoted radiosensitivity enhancement has been shown in radioresistant human prostate cancer cells, because such agent is able to delay DNA- strand break repair together with prolonging cell cycle block. To insightfully understand either microtubule or actin filament meshwork-targeting drug pharmacodynamics, functional cytoskeletal features such as cytoskeleton-related molecule cargo logistics, are preliminary taken into consideration.