Cell cycle perturbations are commonly observed in human malignancies. Exploiting this finding is the rationale for the development of CDK inhibitors as anti-tumor agents. Single-agent evaluation of several CDKIs has demonstrated limited clinical activity. The combination of CDKIs with standard cytotoxic agents is an emerging, alternative approach to anticancer therapy that also exploits the cell cycle perturbations of malignancy. Pre-clinical studies demonstrate the concept of cell cycle mediated drug resistance, and suggest that the combination of standard cytotoxic agents with CDKIs will require thoughtful sequencing and scheduling. With this in mind, there are presently several clinical investigations underway examining the combination of a standard cytotoxic with a novel CDKI, with particular attention to sequence and scheduling. Although phase II evaluation of these combination studies will provide initial evidence of anti-tumor activity, definitive phase III studies will be needed to establish this class of agents in the care of patients with cancer.