Infections of the skin and skin structures in patients at risk can be either primary or secondary. In the normal host, the most important primary dermal pathogens are the group A beta-hemolytic Streptococcus and Staphylococcus aureus. These organisms can spread rapidly and seed to distant sites. Secondary skin involvement occurs in several life-threatening bacteremic conditions in previously normal hosts, especially in those involving meningococci and S. aureus. In the compromised host, although the acute pyogenic bacteria just mentioned can be even more devastating, low grade pathogens or nonpathogenic members of the normal flora, or both, are commonly involved. Such organisms include gram-negative aerobic bacilli, a variety of anaerobes, several fungi, and the herpesviruses. Therapy of primary skin and skin structure infections invariably should include debridement along with antibiotic coverage. Debridement must be complete, opening all deep extensions of the primary infection and removing, to the extent possible, all foreign materials. In the normal host, antibiotic coverage must include a beta-lactamase-resistant antibiotic or vancomycin if beta-lactamase-resistant, antibiotic-resistant S. aureus could be involved. In the compromised host, signs of local inflammation may be reduced; yet, debridement must still be aggressive and antibiotic coverage broad. Neutropenic patients should be covered for Pseudomonas aeruginosa, requiring a combination of an antipseudomonal agent plus an aminoglycoside. Antifungal or antiviral therapy, or both, should be added in the severely compromised host in the proper setting, especially in patients not promptly responding to antibacterial measures. Attempts to enhance host defenses should be considered.