A diverse group of proteins, the activities of which are precisely orchestrated during mitosis, have emerged as targets for cancer therapeutics; these include the Aurora kinases (AKs), Polo‐like kinases (PLKs), and the kinesin spindle protein (KSP). KSP is essential for the proper separation of spindle poles during mitosis. Agents that target KSP selectively act on cells undergoing cell division, which means that KSP inhibitors are mitosis‐specific drugs, and have demonstrated remarkable activities in vitro. However, a significant obstacle to the success of KSP inhibitors is that these compounds, with tremendous efficacy in vitro, have demonstrated little or even no antitumor activity in vivo. Accumulated data suggest that a combination of KSP inhibitors with various cytostatic drugs will result in a more powerful tumor‐killing effect than monotherapy. Combination therapies might predominate and represent the next frontier in the discovery research of KSP inhibitors as potential anticancer drugs. Few published studies have reviewed combination therapy using KSP inhibitors. Herein we provide a comprehensive review of the literature on KSP inhibitor monotherapy and therapeutic combinations. The current state and problems are also discussed. Two are better than one: Targeted therapies in the form of antibodies and small molecules have been studied in combination with kinesin spindle protein (KSP) inhibitors to enhance their efficacy against cancer in preclinical investigations. Accumulated data suggest that a combination of KSP inhibitors with various cytostatic drugs will result in a more powerful tumor‐killing effect than monotherapy. Combination therapies may predominate and represent the next frontier in discovery research for KSP inhibitors as potential anticancer drugs.