Since its proposal three decades ago, the evidence in favor of the somatomedin hypothesis has been compelling. It is clear that somatotrophic actions of growth hormone are mediated through generation of insulin-like peptides and interaction of these peptides with plasma membrane receptors on sensitive cells. It is possible that such actions result from effects of circulating insulin-like peptides and/or insulin-like peptides generated in proximity to their sites of action (autocrine or paracrine effects). Most or all of circulating somatomedin activity in humans can be accounted for by insulin-like growth factors I and II (IFGs I and II). These peptides have considerable structural homology with insulin but, unlike insulin, they circulate in tight, noncovalent association with specific carrier protein. Levels of circulating IGF I and IGF II are affected by growth hormone, but the former peptide is the more sensitive to growth hormone. Levels of circulating IGF I in humans are low at birth, rise progressively during childhood, and peak during midadolescence. The increase in stature that occurs normally during adolescence probably results from this increase in circulating IGF I. Following adolescence, levels of circulating IGF I fall progressively as a function of age. There is good evidence that the reduction in levels of circulating IGF I is related to decreased secretion of growth hormone that accompanies aging. Although it has been suggested that decreased function of the growth hormone-somatomedin axis may cause changes in anabolic indices that accompany the aging process, definitive proof for this hypothesis is lacking. In contrast to IGF I, circulating IGF II reaches "adult" levels early in childhood, and changes are relatively small as a function of increasing age. Counterparts of IGF I and IGF II are present in rats. Dynamics of the growth hormone-somatomedin axis are similar in rats and humans for IGF I. In contrast, levels of IGF II in rat fall precipitously following birth, suggesting a role for rat IGF II in fetal growth and development. The rat has been used as an experimental animal to define the role of the growth hormone-somatomedin axis in aging. As in human studies, no firm relationship between somatomedins and aging has been established in the rat.