Gonadotropin releasing hormone (GnRH) is a hypothalamic decapeptide that binds to GnRH receptors on pituitary gonadotrope cells to modulate the synthesis and secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These gonadotropins in turn regulate gonadal steroidogenesis and gametogenesis. Chemical characterization and structure-activity analysis of GnRH variants containing systematic amino acid substitutions led to the discovery of GnRH superagonists and antagonists. These peptides are widely used for the treatment of clinical conditions in which modulation of or interference with sex hormone production is beneficial to prevent development or progression of benign conditions (e.g. endometriosis, uterine fibroids) or malignant tumors (e.g. breast, ovarian, endometrial and prostate carcinoma). When compared to native GnRH, GnRH superagonists have increased potency for the short-term release of gonadotropins. However, they show paradoxical action in that chronic treatment with superagonists results in inhibition of gonadotropin production as a result of desensitization of the gonadotropes and down regulation of its receptor. In contrast, GnRH antagonists produce a rapid and dose-dependent suppression of gonadotropin release by competitive blockade of the GnRH receptors without any initial stimulatory effect as seen with superagonists. In recent years, a search for peptidomimetic compounds to replace peptides as therapeutic agents has been undertaken to find compounds with higher affinity for the GnRH receptor but do not have the disadvantages of peptides. Such efforts have resulted in the identification and development of small-molecule non-peptide compounds that are sufficiently stable in vivo and possess favorable pharmacological parameters comparable to peptide antagonists. Some of these compounds are being tested in human volunteers and the preliminary results are very encouraging.