This chapter discusses the experimental methodologies that resulted in the discovery of growth hormone antagonists (GHAs). It also examines the in vitro and in vivo data that led to the approval of clinical use of GHA (pegvisomant). The structure-function analysis of growth hormone (GH) resulted in the discovery of a growth hormone antagonist. The antagonistic activity of the GH analogs provides the basis for development of the GHA as a new type of drug. The GHA competes with native GH and inhibits its proper or functional binding to and activation of GH receptors. Subsequent development of a Pegvisomant resulted in a novel drug for the treatment of acromegalic individuals. The ability of Pegvisomant to normalize elevated circulating IGF-I levels in patients with acromegaly serves as a new therapeutic approach toward this disorder. Furthermore, the chapter illustrates the potential role of GHAs in the treatment of certain types of cancer, as an insulin sensitizer, and in treatment of diabetes end organ damage.