Allergy to penicillin is the most commonly reported antibiotic allergy. However, most patients who report a positive history of a prior reaction to penicillin are not found to be allergic to penicillin upon skin testing. Often, this history is vague or based on a parent's recollection of an event that occurred in the distant past. Avoidance of penicillin based on self-reported allergic history alone often leads to the use of an alternate antibiotic with greater cost or side effect profile. Patients with a negative skin test to both major and minor determinants may generally be given penicillin, with a statistical risk of developing an allergic reaction similar to that observed in the general population. A more cautious approach in these cases where the degree of suspicion is low, an allergic etiology is unproven, or there is a negative skin test, is to do a graded challenge. If the skin test is positive, an alternate antibiotic should be used. If, however, an alternate antibiotic is not available, then desensitization may be performed, but there are limitations to desensitization as well, and tolerance is not permanent. Avoidance of cephalosporins may be recommended in cases of penicillin allergy, but newer generation cephalosporins have demonstrate less cross-reactivity to penicillin than earlier generation ones. Desensitization protocols for cephalosporins are available but not standardized. The mechanisms of antibiotic sensitization are not clearly understood.