Although toxicants may initiate cell damage or stress, the cellular proteins that are involved in control of cell cycle and apoptosis are the final arbiters of cell fate. The biochemical pathways that restrain cell cycle transition and/or induce cell death after stress are known as cell cycle checkpoints. These checkpoints maintain the fidelity of DNA replication, repair, and division. Herein, select cell cycle checkpoint signaling pathways will be discussed and how different components of these pathways are regulated by exogenous and endogenous agents, with focus on the p53 tumor suppressor signaling. The p53 protein is known to play a key role in growth arrest and apoptosis after cell stress, primarily through its ability to regulate the transcription of select downstream target genes in the cell. Further elucidation of the signaling pathways that control growth arrest and apoptosis will continue to provide insights to the complex cellular responses to environmental toxicants.