This review summarizes the experimental data demonstrating the fundamental role of kisspeptins and their G protein-coupled receptor GPR54 in the control of reproduction, with special emphasis on their function at puberty. Kisspeptins, products of the KiSS-1 gene, were originally identified as metastasis suppressor peptides with the ability to bind G protein-coupled receptor GPR54. In late 2003, loss-of-function mutations of the GPR54 gene were found in patients suffering from hypogonadotropic hypogonadism. This finding kicked off the analysis of the role of the KiSS-1/GPR54 system in the control of reproduction. Kisspeptins are very potent elicitors of gonadotropin secretion, primarily through stimulation of gonadotropin-releasing hormone release. Enhanced expression of KiSS-1 and GPR54 genes, as well as increased GPR54 signaling, are detected at the hypothalamus during pubertal development, and activation of GPR54 by administration of kisspeptin is sufficient to induce precocious activation of the gonadotropic axis in immature rodents and monkeys. Hypothalamic KiSS-1 also functions as an essential integrator for peripheral inputs, including gonadal steroids and nutritional signals, controlling gonadotropin-releasing hormone and gonadotropin secretion. Kisspeptins and their putative receptor, GPR54, have recently emerged as indispensable factors for pubertal development, with a key role as gatekeepers of gonadotropin-releasing hormone release neurons and, hence, of reproductive function.