The concept of combining chemotherapeutic agents to increase cytotoxic efficacy has evolved greatly over the past several years. The rationale for combination chemotherapy has centered, in the past, on attacking different biochemical targets, overcoming drug resistance in heterogeneous tumors, and by taking advantage of tumor growth kinetics with increasing the dose-density of combination chemotherapy. The overall goal was to improve clinical efficacy with acceptable clinical toxicity. With our increased understanding of the cell cycle and the impact chemotherapeutic agents have on the cell cycle, it is increasingly apparent that this physiology can create drug resistance, thereby reducing combination chemotherapeutic efficacy. This is particularly relevant with the advent of cell cycle-specific inhibitors but also has relevance for the action of standard chemotherapeutic agents currently in clinical practice. This cell cycle-mediated resistance may be overcome by a greater understanding of chemotherapeutic cell cycle effects and by appropriate sequencing and scheduling of agents in combination chemotherapy. In this review, we have elected to illustrate the evolving concept of cell cycle-mediated drug resistance with novel drug combinations that include the taxanes, camptothecins, and fluorouracil. This review indicates that as our understanding of the cell cycle grows, our ability to appropriately sequence chemotherapy to overcome cell cycle-mediated drug resistance can have a great impact on our therapeutic approach in the treatment of human cancers.