Recent analysis of clinical data and a clearer understanding of the role of chemical structure in the development of cross-reactivity indicate that the increased risk of an allergic reaction to certain cephalosporins in penicillin-allergic patients is smaller than previously postulated. Medline and EMBASE databases were searched using the following keywords: cephalosporin, penicillin, allergy, and cross-sensitivity for the years 1960 to 2005. Among 219 articles retrieved, 106 served as source material for this review. A significant increase in allergic reactions to cephalothin, cephaloridine, cephalexin, cefazolin, and cefamandole was observed in penicillin-allergic patients; no increase was observed with cefprozil, cefuroxime, ceftazidime, or ceftriaxone. Clinical challenges, skin testing, and monoclonal antibody studies point to the paramount importance of similarities in side chain structure to predict cross-allergy between cephalosporins and penicillins. First-generation cephalosporins have a modest cross-allergy with penicillins, but cross-allergy is negligible with 2nd- and 3rd-generation cephalosporins. Particular emphasis is placed on the role of chemical structure in determining the risk of cross-reactivity between specific agents.