The advent of molecularly targeted drug discovery has facilitated the identification of a new generation of anti-mitotic therapies that target proteins with specific functions in mitosis. The exquisite selectivity for mitosis and the distinct ways in which these new agents interfere with mitosis provides the potential to not only overcome certain limitations of current tubulin-targeted anti-mitotic drugs, but to expand the scope of clinical efficacy that those drugs have established. The development of these new anti-mitotic drugs as targeted therapies faces significant challenges; nevertheless, these potential therapies also serve as unique tools to dissect the molecular mechanisms of the mitotic-checkpoint response.