Cellular division is an ordered, tightly regulated process involving multiple checkpoints that assess extracellular growth signals, cell size and DNA integrity. Progression throughout the cell cycle is based on the activation of different CDK-cyclin complexes that prevent cells from entering into a new phase until thay have successfully complete the previous one. In addition, a series of cell cycle checkpoints are designed to preserve genome integrity and chromosomal stability. Neoplastic lung cells develop the ability to bypass several of these checkpoints, and tumor cell proliferation is frequently associated with genetic or epigenetic alterations in key regulators of the cell cycle. The goal of this review is to summarize the knowledge about the dysregulation of major cell cycle regulators in lung cancer pathogenesis and to discuss the use of these proteins as targets for therapeutic intervention.