We have gained new insights into the growth-promoting and metabolic actions of IGF over the last few years primarily from studies of children with GHIS (70-74, 76-78). Prolonged therapy with rhIGF-I to children with GHIS and to those with GH gene deletion has proved to be safe and effective with side effects presenting mainly when high doses of rhIGF-I have been used. However, treatment with rhIGF-I given systemically may not completely replace the local response of target tissues to locally produced IGF-I (79). The recent development of rhIGF-I and rhIGFBP-3 led us to perform a pharmacokinetic study comparing the rhIGF-I/IGFBP-3 complex to rhIGF-I in four adolescents with GHIS. The complex induced an increase in serum concentrations of IGF-I within the normal range and was associated with an increased half-life (15–18 h) compared with rhIGF-I (~8 h) (80). A trial of treatment with the rhIGF-I/IGFBP-3 complex in naïve GHIS patients is currently in progress.