With several successful anticancer drugs on the market and numerous compounds in clinical developments, antimitotic agents represent an important category of anticancer agents. However, clinical utility of the tubulin-binding agents is somewhat limited due to multiple drug resistance (MDR), poor pharmacokinetics and therapeutic index. There is ongoing need for the modulators of other intracellular targets that result in the same anti-mitotic effect without adverse effects of "traditional" tubulin binders. This review describes progress made to-date in development of novel and emerging biotargets affecting the mitotic events, and their small-molecule modulators.