A theoretical model is proposed for the description of cell-density dependentproliferation and of phenomena of aging in vitro and applied to heteroploid and diploid fibroblast cultures, respectively. The model is based on the well-accepted subdivision of in vitro cell populations into dividing, reversibly growth-inhibited ( G 0-) and irreversibly growth-inhibited (long-living) cells. Cell-density dependent rate terms for transitions of cells between the three cell compartments are formulated explicitly. In particular it is assumed that (i) the irreversible growth-inhibited cell compartment is populated from the cycling cell compartment, but not from cells “out of cycle”, and (ii) the corresponding transition rate depends supralinearly on the density of irreversibly nonproliferative cells. This autocatalytic feature of the model obviates any necessity of postulating a mitotic counter or asymmetric mitoses to account for in vitro aging and (by implication) cytodifferentiation. The theory is compared with a variety of experiments on repeated subcultivations of diploid fibroblasts using fixed split ratios. Theoretical results describe well the phenomenon of finite life spans in vitro as exhibited by human diploid fibroblasts, as well as the essence of the phenomenon of establishing a permanent cell line after going through a population crisis upon repeated passages, as observed for mouse fibroblasts. The theory is further applied to the description of variation of in vitro life span of fibroblasts from individuals subject to Xeroderma pigmentosum or premature aging and can be shown to resolve the apparent discrepancies between aging in vitro and efficiency of the DNA-repair systems in these cells. In addition, the complex population dynamics of heteroploid cells (suchas 3T3 cells) depending on the states of the seeding population taken at different times after reaching confluency are described in quantitative details by the proposed theoretical model. This suggests that phenomena of irreversible growth inhibition have to be taken into account for these permanent cell lines, too.