Incision and drainage combined with antibiotic therapies form the backbone of managing uncomplicated skin and skin structure infections (uSSSIs). An algorithm has been developed to guide the treatment of uSSSIs in the primary care setting in situations where initial empiric therapy is appropriate. This includes instances when a culture is taken, but it is deemed appropriate to begin an antibiotic empirically pending the results of the culture. The panel that developed the algorithm was chaired by Dr. Richard Scher of Columbia University and included thought leaders in the fields of clinical dermatology, dermatologic surgery, infectious disease, pediatric infectious disease, podiatry, and HIV infection. The panel acknowledged that the initial choice of antibiotic is generally determined by tolerability, ease of administration, cost, and efficacy. The usual choices for initial empiric therapy include cephalosporins, penicillinase-resistant penicillins, and beta-lactam/beta-lactamase inhibitor combinations. Currently marketed cephalosporins, penicillinase-resistant penicillins, and beta-lactam/beta-lactamase inhibitor combinations lack activity against methicillin-resistant Staphylococcus aureus (MRSA), and the increasing prevalence of community-acquired MRSA (CA-MRSA) was a major consideration when designing the treatment algorithm. Many CA-MRSA skin infections present as abscess, and drainage is the most important component of therapy in this setting. When the history and physical exam suggest CA-MRSA infection, and there is no fluctuant collection of purulent material to be drained, a sulfa drug or tetracycline is generally the best choice for initial empiric therapy.