Human tumors arise from multiple genetic changes that gradually transform growth-limited cells into highly invasive cells that are unresponsive to growth controls. The genetic evolution of normal cells into cancer cells is largely determined by the fidelity of DNA replication, repair, and division. Cell-cycle arrest in response to stress is integral to the maintenance of genomic integrity. The control mechanisms that restrain cell-cycle transition or induce apoptotic signaling pathways after cell stress are known as cell-cycle checkpoints. This review will focus on the mechanisms of cell-cycle checkpoint pathways and how different components of these pathways are frequently altered in the genesis of human tumors. As our knowledge of cell-cycle regulation and checkpoints increases, so will our understanding of how xenobiotic agents can affect these processes to either initiate or inhibit tumorigenesis.