Cellular senescence (CS) is a state of stable cell cycle arrest characterized by the production and secretion of inflammatory molecules. Early studies described oncogene-induced senescence (OIS) as a barrier to tumorigenesis, such that the therapeutic induction of CS might represent a rational anti-cancer strategy. Indeed, the validity of this approach has been borne out by the development and approval of the cyclin-dependent kinase (CDK) inhibitor palbociclib for the treatment of breast cancer. Apart from tumors, senescent cells have also been shown to accumulate during natural mammalian aging, where they produce detrimental effects on the physiology of surrounding tissues. Thus, pharmacological senescent cell depletion has been proposed as an approach to delay age-related functional decline; this has been formally demonstrated in animal models. In this review article, we describe the current mechanistic understanding of cellular senescence at the molecular level and how it informs the development of new therapeutic strategies to combat cancer and aging.