The major organisms responsible for skin infections are Staphylococcus aureus and Streptococcus pyogenes. To produce a disease state, both organisms must overcome the body's natural defenses, adhere to the skin, invade the tissue, and proliferate. Often, endogenous skin microflora can lead to systemic infections, especially in immunocompromised individuals. The differential diagnosis of skin infections is key to successful therapy and requires a thorough knowledge of the patient's clinical history and immune status. Laboratory analysis often can assist in the pathogenic differentiation. Examples of common skin infections are illustrated herein.