Cellular senescence is recognized as a critical cellular response to prolonged rounds of replication and environmental stresses. Its defining characteristics are arrested cell-cycle progression and the development of aberrant gene expression with proinflammatory behavior. Whereas the mechanistic events associated with senescence are generally well understood at the molecular level, the impact of senescence in vivo remains to be fully determined. In addition to the role of senescence as an antitumor mechanism, this review examines cellular senescence as a factor in organismal aging and age-related diseases, with particular emphasis on aberrant gene expression and abnormal paracrine signaling. Senescence as an emerging factor in tissue remodeling, wound repair, and infection is considered. In addition, the role of oxidative stress as a major mediator of senescence and the role of NAD(P)H oxidases and changes to intracellular GSH/GSSG status are reviewed. Recent findings indicate that senescence and the behavior of senescent cells are amenable to therapeutic intervention. As the in vivo significance of senescence becomes clearer, the challenge will be to modulate the adverse effects of senescence without increasing the risks of other diseases, such as cancer. The uncoupled relation between cell-cycle arrest and the senescent phenotype suggests that this is an achievable outcome.