Hypothalamic GnRH is the master regulator of the neuroendocrine reproductive axis and its secretion is regulated by many factors. Among these is kisspeptin which is recognized as a potent trigger of GnRH secretion. Kisspeptin signals via KISS1R, a Gɑq/11-coupled seven transmembrane-spanning receptor. Prior to this study, it was understood that KISS1R mediates GnRH secretion via the Gɑq/11-coupled pathway in an ERK-dependent manner. We recently demonstrated that KISS1R also signals independently of Gɑq/11 via ß-arrestin and that this pathway also involves ERK activation. Since GnRH secretion is an ERK-dependent process, we hypothesized that KISS1R regulates GnRH secretion via both the Gɑq/11- and ß-arrestin-coupled pathways. To test this hypothesis, we measured LH secretion, a surrogate marker of GnRH secretion, in mice lacking either ß-arrestin-1 or ß-arrestin-2. The results revealed that Kp-dependent LH secretion was significantly diminished relative to WT mice (P < 0.001), thus supporting that ß-arrestin mediates Kp-induced GnRH secretion. Based on this finding, we hypothesized Gɑq/11-uncoupled KISS1R mutants like L148S will display Gɑq/11-independent signaling. To test this hypothesis, L148S was expressed in HEK 293 cells and results confirmed that, while strongly uncoupled from Gɑq/11, L148S retained the ability to trigger significant ERK activation following Kp-treatment (P < 0.05). Taken together with the ß-arrestin knockout results, we conclude that KISS1R signals via both Gɑq/11 and ß-arrestin to regulate GnRH secretion. This novel and important finding could explain why patients bearing some types of Gɑq/11-uncoupled KISS1R mutants display partial gonadotropic deficiency.