Based on their mechanism of action, anti-tumor drugs that target the cell cycle can be generally divided into three categories, namely, blocking DNA synthesis, causing DNA damage, and disrupting mitotic processes. In terms of mitotic inhibitors, most compounds used in the clinic impair the normal function of mitotic spindles by targeting tubulins, basic building blocks of microtubules. In vivo, these compounds often exhibit significant side effects, thus limiting their efficacy. Mitotic processes are under tight control through surveillance mechanisms commonly termed checkpoints. Defects in the regulation of these checkpoints often result in genomic instability, which predisposes the cell to malignant transformation. As cancer is the consequence of uncontrolled cell division, great efforts have been devoted to discover drugs that target mitosis, thereby halting cell division and inducing mitotic catastrophe with minimal cytotoxicity to nondividing or normally dividing cells. This review primarily focuses on mitotic proteins that have been explored as new targets for anti-cancer drug development during the past decade.