Growth hormone secretagogues (GHSs) are a class of synthetic compounds that increase growth hormone secretion and serum IGF-1 concentrations. The short-acting GHSs produce transient elevations in GH which lead to little or no changes in IGF-1; the long-acting GHSs stimulate pulsatile GH release due to sustained elevations of IGF-1. GHSs are currently undergoing evaluation as orally active alternatives to the recombinant human proteins, rhGHRH and rhGH. The clinical development of these compounds has been complicated, not by a failure to enhance GH secretion or raise IGF-1 in humans, but by the difficulty of establishing the therapeutic utility of increasing endogenous levels of GH/IGF-1 (as opposed to replacement with exogenous hormone). The phase II/III clinical trials of one GHS, MK0677 (Merck & Co Inc), for the treatment of short-stature in growth hormone-deficient children and frailty in the elderly have been discontinued for lack of sufficient efficacy. This review summarizes recent advances in this new therapeutic area and describes possible future directions.