Normal cells respond to DNA damage, dysfunctional telomeres and other potentially oncogenic events by entering an essentially irreversible state of arrested growth and altered function termed senescence. The senescence response, like the apoptotic response, is an important tumor suppressive mechanism for mammals. In addition, there is increasing evidence that the senescence response may be an example of evolutionary antagonistic pleiotropy and contribute to aging. That is, while this response curtails the development of cancer early in life, the accumulation of dysfunctional senescent cells later in life may cause or promote aging phenotypes and the development certain age-related pathologies, including, ironically, late life cancers. How might senescent cells fuel aging and/or age-related disease? In addition to the irreversible growth arrest, the senescence response is accompanied by many changes in gene expression. Of particular importance, senescent cells secrete a variety of molecules that can alter tissue structure and function, thereby relaxing the ability of the tissue to maintain normal cellular behavior. High-throughput analysis of the secretory phenotype of senescent human and mouse fibroblasts reveals that senescent cell secrete a large number of factors, including matrix remodeling enzymes, epithelial growth factors, inflammatory cytokines, and cytokines that stimulate cell migration and invasion. We find that factors secreted by senescent fibroblasts can stimulate the proliferation of epithelial cells with potentially oncogenic mutations. Moreover, they can also compromise the ability of neighboring normal cells to maintain optimal differentiated tissue structures and functions. Thus, the accumulation of senescent cells may link the decline in tissue function that is a hallmark of aging with the rise in age-related cancer. Can the secretory phenotype of senescent cells be blunted or reversed? We have had limited success in this endeavor. Our recent ability to completely reverse the effects of senescent stromal cells on ductal hyperplasia in a cell culture model of mammary gland morphogenesis support concept that eliminating or reducing the activities of senescent cells may retard age-related decrements in tissue structure and function.