The epothilones are isolated as secondary metabolites from fermentation of a soil myxobacterium, Sorangium cellulosum. These natural products are potent cytotoxic agents that exert their cell-killing effects via microtubule stabilization.� They are particularly attractive as drug leads owing to their unique ability to overcome multiple tumor-resistance mechanisms.� Among the epothilone natural products, Epothilone B has the most compelling in vitro properties.� However, preliminary work in these laboratories suggested that improvements in drug-like properties of the natural product were desirable.� Therefore, a semisynthesis campaign was initiated to prepare optimized epothilone analogs for clinical investigation.� Efficient fermentation of Epothilone B was necessary to provide adequate material for chemical derivatization.� Strain improvements and modifications to the original fermentation process enabled the recovery of Epothilone B as a major metabolite.� Combination of semisynthesis and microbial biotransformation was utilized in the lead optimization phase.� New epothilone analogs were evaluated for in vitro activity and metabolic stability.� Promising leads were evaluated in tumor models in athymic mice. Ixabepilone (BMS-247550), a novel lactam analog, emerged as a superior agent with broad spectrum efficacy against human tumor xenografts.� This robust preclinical activity was recapitulated in early human clinical trials for several cancers, including metastatic breast cancer and prostate cancer.�� Currently, Ixabepilone is in late-stage (i.e., Phase III) clinical trials for metastatic breast cancer.