Body growth is regulated by growth hormone (GH) and insulin-like growth factor-I (IGF-I). The classical somatomedin hypothesis of this regulation is that most IGF-I in the blood originates in the liver and that body growth is controlled by the concentration of IGF-I in the blood. We have recently abolished IGF-I production in the livers of mice by using the Cre/loxP recombination system. These mice displayed a more than 75% reduction in serum IGF-I associated with increased serum levels of GH. In contrast, they demonstrated a normal postnatal growth, indicating that extrahepatic, autocrine/paracrine-acting IGF-I is the main determinant of postnatal growth. Thus, the "classical" somatomedin hypothesis needs revision. We propose the "dual somatomedin hypothesis" according to which: (1) autocrine/paracrine IGF-I is the main determinant of postnatal body growth and (2) liver-derived, endocrine-acting, IGF-I exerts negative feedback on GH secretion and possibly also exerts other effects on carbohydrate and lipid metabolism.