The regulation of reproductive function and fertility is ultimately controlled by a pulsatile signal of gonadotropin-releasing hormone (GnRH). GnRH is synthesized and secreted by a few hundred GnRH neurons in the hypothalamus that work in synchrony to produce this pulsatile rhythm. The mysteries surrounding the rhythmogenesis in GnRH neurons remain defiant to any conventional knowledge of rhythm-generation in neuronal networks. Efforts to crack this puzzle have been pushing the frontier of classical neuroscience that traditionally only focused on ionotropic channel events with time scales of milliseconds to the inclusion of metabotropic receptors, second messengers, vesicle transportation and docking, autocrine/parcrine regulations, as well as genetic events. Mathematical modeling of this rhythm gives rise to challenging nonlinear mathematical problems one has never encountered before. This talk will present a brief summary of important progress in recent years including our own contributions to solving this puzzle.