The kisspeptin system has emerged as one of the most important circuits within the central network governing reproduction. Although kisspeptin physiology has been examined in many species, much of our understanding of this system has come from mice. Recently, the study of several innovative strains of genetically engineered mouse models has revealed intriguing and unexpected insights into the functions of kisspeptin signaling in the hypothalamus. Here, we review the advancements in our knowledge of the central kisspeptin system through the use of mutant mice.