Until recently, development of chemotherapeutic agents that target mitosis has centered on inhibiting the mitotic spindle through interactions with microtubules. The taxanes, while significantly advancing the treatment of many types of cancer, suffer from problems of hematopoeitic and neurologic toxicities, development of resistance, and an inconvenient formulation. Novel microtubule inhibitors currently in clinical trial and in clinical use have the main advantage of overcoming resistance. Still, they have side effects related to the inhibition of microtubules in normal host cells. Novel antimitotics, which target the mitotic spindle through interactions with nonmicrotubule mitotic mediators like mitotic kinases and kinesins, have been identified and are now in clinical trial. They offer the prospect of surmounting more of the problems inherent with taxanes and the hope of improving upon their broad antitumor efficacy. This review will concentrate on novel agents in later clinical development that target both the spindle microtubule and nonmicrotubule constituents of mitosis.