Secondary bacterial skin infections are common complications of primary dermatoses, primary nonbacterial skin infections, traumatic lesions, ulcers, cutaneous infestations, and other miscellaneous skin diseases. Most diagnoses are based on information obtained by patient history and physical examination. Secondary bacterial skin infections may be polymicrobial, commonly include the pathogens Staphylococcus aureus and Streptococcus pyogenes, and require proper antibiotic treatment. The use of topical antibiotics avoids the risk of systemic allergic reactions or generalized side effects, and provides a high antibiotic concentration at the site of infection. Therefore, topical antibiotics should be considered as potential primary therapy in the emergency department. When systemic therapy is indicated, most commonly used agents for secondary skin infections are the penicillinase-resistant semi-synthetic penicillins; the first-generation cephalosporins, the macrolides; and combination antibacterials, such as amoxicillin/ clavulanate potassium and trimethoprim/sulfamethoxazole.