© 2014 by John Wiley & Sons, Inc. All rights reserved. Cellular senescence is classically defined as a state of irreversible growth arrest. It can be broadly classified into the intrinsic (replicative) and extrinsic (premature) pathways. Both extrinsic senescence and intrinsic senescence converge on common signaling pathways that give rise to the typical morphological and biochemical features of cellular senescence. This chapter summarizes the molecular signaling pathways that regulate cell senescence, focusing on transcriptional and mechanistic regulation of these pathways in aging. It discusses how the core signaling pathways, involving the p16 and p53 tumor suppressor genes, are perturbed in cellular senescence. Finally, the chapter proposes the therapeutic approaches to target senescence pathways for the treatment of aging and aging-related diseases. Further work aimed at understanding the role of cell senescence signalling pathways in response to various stimuli may highlight their potential as future drug targets for senescence.