These infections have diverse etiologies that depend, in part, on different epidemiological settings. As a result, obtaining a careful history that includes information about the patient's immune status, geographic locale, travel history, recent trauma or surgery, previous antimicrobial therapy, lifestyle, hobbies, and animal exposure or bites is essential when developing an adequate differential diagnosis and an appropriate index of suspicion for specific etiological agents. Recognition of the physical examination findings and understanding the anatomical relationships of skin and soft tissue are crucial for establishing the correct diagnosis. In some cases, this information is insufficient and biopsy or aspiration of tissue may be necessary. In addition, radiographic procedures may be critical in a small subset of patients to determine the level of infection and the presence of gas, abscess, or a necrotizing process. Last, surgical exploration or debridement is an important diagnostic, as well as therapeutic, procedure in patients with necrotizing infections or myonecrosis and may be important for selected immunocompromised hosts.