In response to various stresses, such as telomere shortening during continuous proliferation, oxidative stress, DNA damage and aberrant oncogene activation, normal cells undergo cellular senescence, which is a stable postmitotic state with particular morphology and metabolism. Signaling that induces senescence involves two major tumor suppressor cascades, i.e., the INK4a-Rb pathway and the ARF-p53 pathway. Diverse stimuli upregulate these interacting pathways, which orchestrate exit from the cell cycle. Recent studies have provided insights into substantial differences in senescence-inducing signals in primary cells of human and rodent origins. This review is focused on recent advances in understanding the roles of the tumor-suppressive pathways in senescence.