Proliferative disorders are a major challenge for human health. The understanding of the organization of cell-cycle events is of the utmost importance to devise effective therapeutic strategies for cancer. The awareness that cells and organisms are complex, modular, hierarchical systems and the availability of genome-wide gene expression and protein analyses, should make it feasible to elucidate human diseases in terms of dysfunctions of molecular systems. Here we review evidence in support of a systems model of the cell cycle, in which two sequential growth-sensitive thresholds control entry into S-phase. The putative molecular determinants that set the threshold for entry into S-phase are consistently altered in cancer cells. Such a framework could be useful in guiding both experimental investigation and data analysis by allowing wiring to other relevant cell modules thereby highlighting the differential responses, or lack of response of cancer cells to intra- and extracellular factors. Pharmacological approaches that take advantage of transformation-induced fragility to glucose shortage are discussed. Extension of this hierarchical, modular approach to tumors as a whole holds promise for the development of effective drug discovery approaches and more efficient therapeutic protocols.