The relative biological importance of plasma levels of insulin-like growth factors (IGFs) is uncertain since the IGFs may act through endocrine mechanisms involving circulating IGFs secreted by the liver, or by autocrine/paracrine mechanisms with IGF production in or close to their target cells. We report here studies in rats designed to examine this problem with an investigation of the changes in plasma and tissue concentrations of IGF-I in relation to the inhibition of bone and muscle growth and proteoglycan synthesis, a putative IGF-I-sensitive process, by protein deficiency. Over a 3-week period in young well-fed growing rats, there were marked increases in plasma IGF-I, whereas in the protein-deficient animals in which growth was inhibited concentrations fell markedly. In bone, concentrations of IGF-I were initially 20% of plasma, did not increase with age and were minimally influenced by protein deficiency. In skeletal muscle, concentrations of IGF-I were initially 3% of plasma, did not increase with age, but did fall with protein deficiency. In bone, the inhibition of proteoglycan synthesis by the protein deficiency was not correlated with changes in tissue IGF-I concentrations and was poorly correlated with changes in plasma hormone concentrations, although in the latter case an exponential relationship could be fitted to the data from the initial control and subsequent protein-deficient animals. In muscle, the changes in proteoglycan synthesis were significantly linearly correlated with changes in tissue IGF-I compared with an exponential relationship with plasma concentrations from the initial control and subsequent protein-deficient animals. These data demonstrate that neither plasma IGF-I concentrations nor the level of total extractable tissue IGF-I can be assumed to be unequivocal determinants of IGF-I status.