The eukaryotic cell cycle is tightly regulated by the sequential activation and deactivation of the cyclin-dependent kinases (CDKs). Aberrant CDK activity is a common defect in human tumours, and clinically, it often confers a poor prognosis. The strong genetic link between CDKs and the molecular pathology of cancer has provided the rationale for developing small-molecule inhibitors of these kinases. X-ray crystallography recently has revealed the molecular details of CDK regulation by cyclin binding and phosphorylation, and by complex formation with endogenous inhibitors. Knowledge of the structure of CDK2 has been key in driving the design and development of a large number of ATP competitive inhibitors. Crystallography has revealed that the ATP-binding site of CDK2 can accommodate a number of diverse molecular frameworks, exploiting various sites of interaction. In addition, residues outside the main ATP-binding cleft have been identified that could be targeted to increase specificity and potency. These results suggest that it may be possible to design pharmacologically relevant ligands that act as specific and potent inhibitors of CDK activity. We provide a review of the current state of the field, along with an overview of our current inhibitor design studies.