When the work load presented to an organ increases, its functional response is proportionately augmented, a finding that forms one of the self-evident truths of homeostasis. For large and chronic increases in work load, homeostasis is often maintained by an increase in the number of functioning units. For example, in breast tissue, new acini develop during lactation, and similarly, chronic hypoxia induces an increase in the number of erythrocytes. However, in many organs, there is a predetermined limit to the total number of functioning units. For instance, in the kidney and lung, the number of nephrons and alveoli is set early in life, and no matter how high the demand, that number of functional units does not increase. Similarly, in response to increased work loads, there are no increases in the number of fibers in cardiac and skeletal muscle or in the number of absorptive villi in the intestine. The inability to reinitiate the developmental processes responsible for functional unit generation ‘‘forces’’the organ to hypertrophy, ie, to increase the physical size of the unit to increase work capacity. The signaling mechanism or mechanisms that initiate the hypertrophic growth process remain elusive. However, it is known that, after removal of one kidney, compensatory hypertrophy is mediated by more than just the increase in the filtration rate. More recently, it was discovered that a reduced number of functioning nephrons leads to an inexorable loss of the function of those remaining (1–3). Similarly, pressure-overload hypertrophy of the heart is associated with a progressive decline in its mechanical function (4, 5). Somewhat counterintuitively, limiting the compensatory growth response in these conditions is beneficial and has led to many of the recent advances in therapeutics. The growth response to loss of renal mass depends on the amount of tissue loss. After the removal of one kidney, the resulting growth pattern is one of hypertrophy (increase in cell size) without hyperplasia (increase in cell number; ref. 6). This hypertrophy primarily involves the proximal tubules and correlates with an increase in kidney weight. In contrast, removal of more than one kidney, the so-called five-sixths nephrectomy remnant-kidney model that was used in the paper by Megyesi et al.(7), leads to a combination of hyperplasia and kidney enlargement; the kidney enlargement presumably reflects hypertrophy of the remaining nephrons. This observation suggests that the hyperplasia is induced by the renal injury, whereas the hypertrophy is associated with the increased demand for work capacity. A similar scenario exists for the glomerulus, in which hyperplasia is associated with glomerular injury but not with a reduction in glomerular number per se. Remarkably, cell-cycle proteins seem to be involved in both hypertrophy and hyperplasia (6). Hence, the availability of mice lacking one or another of these critical factors presents an opportunity, heretofore unavailable, to break into this complex pathway and examine its role in the genesis of progressive kidney failure induced by reduction in nephron mass. Megyesi et al.(7) have examined this progressive decline in kidney function in mice lacking p21WAF1/CIP1 (p21), an inhibitor of the cyclin G1 kinase. Removal of 80% of the kidney mass from wild-type mice results (as expected) in glomerular and tubular enlargement and eventual sclerosis and failure of the remaining nephrons. Remarkably, the mutant mice did not develop sclerosis or renal failure. They develop all of the characteristic changes associated with compensatory hypertrophy: their glomerular filtration rate increases initially, and their glomeruli enlarge, as does whole-kidney mass …