Tubulin poisons were first discovered decades ago, but the recent clinical and commercial success of Taxol has led to a renaissance in the search for novel mitotic spindle poisons to treat cancer. Many tubulin poisons have been identified, but few have demonstrated clinical utility. Recent studies have begun to identify the factors that differentiate the efficacy of these agents. In addition, promising alternative approaches to targeting the mitotic spindle have been identified from detailed studies of mitotic regulation and mechanics.