Hidradenitis suppurativa (HS) is a frequently devastating inflammatory skin disorder. Although many treatments have been tried and tested to date, there is only one Food and Drug Administration-approved treatment option, adalimumab, which is currently indicated for moderate-to-severe HS. Our understanding of the management of HS with biologic agents and with nonantibiotic and/or antimicrobial systemic therapies continues to evolve. In this article, we summarize the existing data on biologics and other small-molecule systemic agents, as well as share our personal experiences with the pharmacological management of HS in the clinical setting. Continued challenges that limit our ability to study and treat this disease effectively include a lack of a universally employed scoring system for disease severity, high variability in clinical presentation, high cost of off-label therapy, and the scarcity of long-term studies on treatment response and medication safety.