Many organisms, including humans, have evolved dynamic social behaviors to promote survival. Public health studies show that isolation from social groups is a major risk factor for adverse health outcomes in humans, but these studies lack mechanistic understanding. Animal models can provide insight into the molecular and neural mechanisms underlying how social isolation impacts health through investigations using genetic, genomic, molecular, and neuroscience methods. In this review, we discuss Drosophila melanogaster as a robust genetic model for studying the effects of social isolation and for developing a mechanistic understanding of the perception of social isolation and how it impacts health.