Primary mammalian cells have a finite life span in tissue culture, suggesting that there may be intrinsic mechanisms that count cell divisions, and that cellular “senescence” may reflect aspects of organismal aging. Both human and mouse cells have been used to study replicative growth arrest, although each system has its peculiarities. Human fibroblasts, for example, have a more extended proliferative potential than their mouse counterparts in culture, yet rarely become adapted to continuous growth as permanent cell lines (“establishment”). They are more resistant than rodent cells to oncogene-mediated transformation and tend to be more stable chromosomally. Despite these obvious differences, the temptation has been to link conclusions drawn from studies in these different cell systems, equating senescence in mouse and human cells. Here, we consider the idea that senescence of cultured cells results from two sources of signals, either of which can induce the expression of a common set of inhibitors of the cell division cycle. One set of triggers is extrinsic and stems from stresses that cells experience when they are explanted into culture (“culture shock”). The second class is intrinsic and depends instead upon the machinery that monitors the integrity of chromosomal telomeres (a potential “mitotic clock”). We suggest that differences in the proliferative capacity of cultured mouse and human cells reflect the extent to which they respond to these signaling pathways.