Hidradenitis suppurativa (HS) is a chronic, relapsing, and remitting inflammatory disease of the skin with significant heritability and racial disposition. The pathogenesis of HS remains enigmatic, but occlusion of the terminal hair follicle and dysregulation of the local innate immune response may contribute to pathogenesis. Genetic predisposition might also contribute to disease susceptibility and phenotypic heterogeneity because mutations in γ-secretase have been found to underlie a minor but characteristic subset of patients with HS. In this review, we synthesized the current data on γ-secretase in HS, evaluated its importance in the context of disease pathobiology, and discussed avenues of future studies.