Background Recent research has shown that a large majority of patients with a history of penicillin allergy are acutely tolerant of penicillins and that there is no clinically significant immunologic cross-reactivity between penicillins and cephalosporins or other β-lactams. The standard test to confirm acute tolerance is challenge with a therapeutic dose. Skin testing is useful only when the culprit antibiotic can haptenate serum proteins and induce an immunoglobulin E–mediated reaction and the clinical history demonstrates such high risk that a direct oral challenge may result in anaphylaxis. Objective To review and evaluate the current practice of skin testing for antibiotics (other than penicillin) in critically ill patients by means of a systematic literature review. Methods This systematic review was performed using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. Several electronic databases were searched using the following terms: antibiotics, skin test (tests, testing) , intensive care, intensive care unit, ICU, critical care, critical care unit . Results Twenty-three articles were identified for inclusion in this review. The results indicate a lack of standardized skin testing for all antibiotics in critical care settings. Oral challenge with nonirritating concentrations of antibiotics can be helpful in determining allergy to these drugs. Conclusions Critical care providers should evaluate antibiotic allergy using nonirritating concentrations before administering antibiotics to patients. Introduction of a standardized skin test for all antibiotics in intensive care unit patients to help select the most appropriate antibiotic treatment regimen might help save lives and reduce costs.