Prolonged social isolation has been reported to be one of the risk factors for human health, equivalent to smoking cigarettes. Therefore, some developed countries have recognized prolonged social isolation as a social problem and have started to address this problem. Studies on rodent models are essential to fundamentally clarify the impacts of social isolation on human health mentally and physically. In this review, we conduct an overview of the neuromolecular mechanisms of loneliness, perceived social isolation, and the effects of prolonged social isolation. Finally, we consider the evolutionary development of neural bases of loneliness.