As demonstrated in Table 2, the differential diagnosis of growth hormone insensitivity (GHI) includes a number of discrete disorders that can be broadly classified as primary or secondary forms. We have selected GHRD (Laron syndrome) as the prototypic disorder of GHI, in part because such dramatic and rapid progress has been made in this clinical condition over the last 6 yr. These advances represent the fortunate convergence of: 1) the cloning of the GHR gene and the identification of deletions and mutations of this gene in GHRD; 2) the development of assay methods for measurement of the GHBP, IGF peptides, and binding proteins; 3) the discovery of a larger number of affected individuals than had been previously suspected, including the recognition and description of a large genetically homogeneous population of GHRD patients in Ecuador; and 4) the production of recombinant IGF-I for therapeutic trials in GHRD. Although we are still in the early phases of clinical trials of recombinant hIGF-I in GHRD, preliminary results have been encouraging. Whether this promise translates into genuine improvements in height and body composition, without significant clinical toxicity, remains to be determined. Similarly, the suitability of IGF-I therapy for other, particularly secondary, forms of GHI is still uncertain, although the responsiveness of GHD-IA patients seems to parallel that seen in GHRD (66, 78). The next few years should provide exciting and potentially important new data on the clinical spectrum, biochemical and molecular characteristics, and responsiveness to therapy of syndromes of GHI.