The third chapter addresses microtubule stabilizers, which are a mainstay in the treatment of many solid cancers and are often used in combination with molecularly targeted anticancer agents and immunotherapeutics. The taccalonolides are a unique class of such microtubule stabilizers isolated from plants of Tacca species that circumvent clinically relevant mechanisms of drug resistance. Although initial reports suggested that the microtubule stabilizing activity of the taccalonolides is independent of direct tubulin binding, additional studies have found that potent C-22,23 epoxidated taccalonolides covalently bind the Aspartate 226 residue of ß-tubulin and that this interaction is critical for their microtubule stabilizing activity. Some taccalonolides have demonstrated in vivo antitumor efficacy in drug-resistant tumor models with exquisite potency and long-lasting antitumor efficacy as a result of their irreversible target engagement. The recent identification of a site on the taccalonolide scaffold that is amenable to modification has provided evidence of the specificity of the taccalonolide-tubulin interaction and the opportunity to further optimize the targeted delivery of the taccalonolides to further improve their anticancer efficacy and potential for clinical development.