Dermatologists treat a variety of uncomplicated skin and skin structure infections (uSSSIs) such as folliculitis, impetigo, erysipelas, cellulitis, furuncles, carbuncles, and non-perirectal abscesses. Most uSSSIs are caused by Staphylococcus aureus and Streptococcus pyogenes. The new extended-spectrum cephalosporins (cefdinir, cefpodoxime) offer efficacy against most Gram-positive and Gram-negative pathogens. Despite recently published guidelines, many physicians do not prescribe cephalosporins for uSSSIs out of concern that these agents will produce a hypersensitivity reaction in patients allergic to penicillin. Although the rate of cephalosporin reaction in penicillin-allergic patients is often quoted as up to 10%, this rate does not take into account the 1% to 3% risk for allergy to cephalosporin alone and the nonspecific increased risk of penicillin-allergic patients to develop hypersensitivity to other drugs. When these additional risks are considered, the likelihood of a reaction in known penicillin-allergic patients, especially to most third-generation and extended spectrum cephalosporins, becomes less than 1%. Cephalosporins with side chains unlike those of penicillin or ampicillin side chains are less likely to result in an allergic reaction in penicillin or ampicillin-allergic patients than cephalosporins with similar side chains. Although both cefdinir and cefpodoxime are considered to carry a very low risk of cross reactivity with penicillin or ampicillin, the former demonstrates better activity against S. aureus. Among the late-generation cephalosporins, cefdinir is the most potent oral agent when tested against oxacillin-susceptible staphylococci, 4- to 16-fold more active than cefprozil and cephalexin, respectively.