Necrotizing soft-tissue infections (NSTIs) are highly lethal. They are frequent enough that general and specialty physicians will likely have to be involved with the management of at least 1 patient with NSTI during their practice, but they are infrequent enough that familiarity with the disease will seldom be achieved. Establishing the diagnosis of NSTI can be the main challenge in treating patients with NSTI, and knowledge of all available tools is key for early and accurate diagnosis. The laboratory risk indicator for necrotizing fasciitis score can be helpful for distinguishing between cases of cellulitis, which should respond to medical management alone, and NSTI, which requires operative debridement in addition to antimicrobial therapy. Imaging studies are less helpful. The mainstay of treatment is early and complete surgical debridement, combined with antimicrobial therapy, close monitoring, and physiologic support. Novel therapeutic strategies, including hyperbaric oxygen and intravenous immunoglobulin, have been described, but their effect is controversial. Identification of patients at high risk of mortality is essential for selection of patients that may benefit from future novel treatments and for development and comparison of future trials.