Medication hypersensitivity is a constant variable that podiatric physicians face during their professional day. To avoid potential patient harm, an understanding of penicillin and cephalosporin hypersensitivities as it pertains to podiatric medicine needs to be achieved. To accomplish this, a narrative describing the signs, symptoms, and immunologic mechanisms for the basis of penicillin and cephalosporin drug hypersensitivities is presented. Second, specific medical literature serving as clinical-based evidence to support the prescribing of cephalosporins in patients with documented penicillin allergy is presented. Finally, a review of the medical and legal literature describing health-care provider liability regarding subsequent drug hypersensitivity is presented. The information contained in this review allows for the evolving paradigm that permits the prescribing of selective cephalosporins to patients with a history of penicillin allergy as long as the allergic symptoms were not serious or life-threatening. (J Am Podiatr Med Assoc 98(6): 479–488, 2008)

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