Severe skin and soft tissue infections (SSTIs) frequently require management in the ICU, in part related to associated septic shock or toxic shock syndrome or associated organ failure. Four fundamental management principles are key to a successful outcome in caring for patients who have severe SSTIs, including (1) early diagnosis and differentiation of necrotizing versus nonnecrotizing SSTI, (2) early initiation of appropriate empiric broad-spectrum antimicrobial therapy with consideration of risk factors for specific pathogens and mandatory coverage for methicillin-resistant Staphylococcus aureus (MRSA), (3) source control (ie, early aggressive surgical intervention for drainage of abscesses and debridement of necrotizing soft tissue infections), and (4) pathogen identification and appropriate de-escalation of antimicrobial therapy. MRSA has emerged as the most common identifiable cause of severe SSTIs; therefore, initiation of empiric anti-MRSA antimicrobials is warranted in all cases of severe SSTIs. In addition, appropriate critical care management-including fluid resuscitation, organ support and nutritional support-is a necessary component in treating severe SSTIs.