Colorectal cancer (CRC), one of the most common malignancies worldwide, is often diagnosed at an advanced stage, and resistance to chemotherapeutic and existing targeted therapy is a major obstacle to its successful treatment. New targets that offer alternative clinical options are therefore urgently needed. Recently, perturbation of the spindle assembly checkpoint (SAC), the surveillance mechanism that maintains anaphase inhibition until all chromosomes reach the metaphase plate, has been regarded as a promising target to fight cancer cells, either alone or in combination regimens. Consistent with this strategy, many cancers, including CRC, exhibit altered expression of SAC genes. In this article, we review our current knowledge on SAC activity status in CRC, and on current anti-CRC strategies and future therapeutic perspectives on the basis of SAC targeting experiments in vitro and in animal models.