Puberty is the end-point of a complex series of developmental events, defined by the dynamic interaction between genetic factors and environmental cues, ultimately leading to the attainment of reproductive capacity. The neuroendocrine basis of puberty has been the subject of extensive investigation in the last decades, and identification of the trigger(s) of puberty onset has drawn considerable attention. In this context, recognition of the fundamental role of kisspeptin (encoded by the KiSS-1 gene) and its receptor GPR54 as major gatekeepers of gonadotropic function in general, and puberty onset in particular, has been a major breakthrough in contemporary Neuroendocrinology. Indeed, during the last 3 years, the so-called KiSS-1/GPR54 system has been substantiated as pivotal regulator of puberty in mammals; the lack of GPR54 signaling being coupled to sexual immaturity (impuberism) in mice and humans. In this review, we will summarize the most salient experimental data (mostly obtained in laboratory animals) demonstrating the key roles of hypothalamic KiSS-1 neurons in the activation of the reproductive axis at puberty, and its regulation by metabolic and, eventually, environmental factors. Whether the KiSS-1 system is the trigger for puberty onset and/or it operates as integrator and effector of up-stream regulatory factors warrants further investigation.