Human cancer can arise due to inherited and sporadic genetic and epigenetic changes. These changes consequently inhibit the function of tumor suppressors and pro-apoptotic genes, while activate oncogenes. Most human cancers arise as benign tumors; after acquiring additional genetic and epigenetic changes, they become malignant and eventually metastasize to distal organs. Recent studies have implicated multiple tumor suppressing mechanisms that prevent neoplastic transformation and thus have anti-cancer activities. Among these, cellular senescence has emerged as an important tumorigenesis regulatory mechanism, which not only modulates tumor initiation but also affects tumor progression and maintenance. Cellular senescence is also observed in response to genotoxic chemotherapeutic agents and has been linked to cancer recurrence and drug resistance. Thus improved understanding of regulators of chemotherapy-induced cellular senescence will allow us to explore rational and targeted therapies against various human cancers. In this review, we aim to describe the mechanisms and regulation of three major forms of cellular senescence: replicative senescence (RS), oncogene-induced senescence (OIS) and accelerated cellular senescence (ACS). We also discuss the role of cellular senescence in human cancer and high-throughput genomics-based methods to identify the regulators of cellular senescence. Finally, we highlight aspects of cellular senescence that could be targeted for alternative, yet viable cancer therapies against a variety of human cancers. © 2010 Landes Bioscience.