Research over the last 40 years has led to a detailed model of eukaryotic cell cycle control. A beautiful logic underlies these molecular controls. Each regulatory event has two important functions: to activate a step of the cell cycle and to prepare the cell for the next event of the cycle. This strategy ensures that the phases of the cycle occur in the proper order.

Although the general logic of cell cycle regulation now seems well established, many critical details remain to be discovered. For instance, how cell growth and division are coordinated, and how the metabolic state of a cell feeds into its cell cycle machinery, remain to be discovered. A number of key nutrient- and growth factor–sensing pathways, such as the AMPK, Ras, and TOR pathways, have been identified and their inner workings revealed. How they affect the cell cycle machinery will be a critical question to be addressed in the years to come. Substantial progress has been made recently in identifying the substrates phosphorylated by different CDKs, but much work remains to be done to understand how the modification of these proteins leads to the multiple events that these CDKs trigger.

Much has been discovered recently about the operation of cell cycle checkpoint pathways, but the mechanisms that activate ATM and ATR in the DNA damage checkpoint pathway are poorly understood. Likewise, much remains to be learned about the control and mechanism of regulation of Mad2 in the spindle assembly checkpoint pathway. Many questions remain about how the plane of cytokinesis and the localization of daughter chromosomes are determined in cells that divide asymmetrically, as is often seen as part of the development of complex tissues and organ structures. How the cell cycle machinery is modulated by developmental cues to bring about specialized divisions is also an intense area of investigation.

Understanding these detailed aspects of cell cycle control will have significant consequences, particularly for the treatment of cancers. Cancer cells often have defects in cell cycle inhibitory mechanisms and cell cycle checkpoint pathways that lead to the accumulation of multiple mutations and DNA rearrangements that result in the cancer phenotype. If more were understood about cell cycle controls and checkpoint pathways, it might be possible to design ever more effective therapeutic strategies, especially against types of cancer that are largely resistant to today’s conventional therapies. It seems very likely that better understanding of the molecular processes involved will allow the design of more effective treatments in the future.