Cyclin-dependent kinases (CDKs) are a family of protein kinases that regulate progression through the eukaryotic cell cycle. Aberrant CDK activity or function is a common defect in human tumours, resulting in unrestrained cellular proliferation. X-ray crystallographic analysis of monomeric CDK2 and CDK2 complexes has revealed how phosphorylation and cyclin binding mediate enzyme activation and how this activity can be regulated by further protein association. Current research aims to improve the selectivity and/or potency of small molecule CDK inhibitors, both to develop specific probes to study the roles of the different CDK family members in coordinating cell cycle progression, and as lead molecules for the design of therapeutically useful drugs. This design process has been assisted by the availability of a number of CDK2/inhibitor structures determined using X-ray crystallography. These structures have shown that molecules related to ATP can be accommodated in the ATP-binding site in a number of orientations, utilising interactions observed between CDK2 and its natural ligand, as well as novel interactions with CDK2 residues that lie both within and outside the active site cleft. This site can also bind inhibitors that are structurally unrelated to ATP. These results suggest that it may be possible to design pharmacologically and pharmaceutically important ATP-binding site-directed ligands that act as specific and potent inhibitors of CDK activity.