Penicillin allergy is the most commonly reported drug allergy in the United States. However, after undergoing a complete evaluation by a board-certified allergist, including skin testing, 90% of patients labeled as 'penicillin-allergic' are able to tolerate penicillin. Clinical presentation is key in classifying reactions as either mediated by or not mediated by immunoglobulin E (IgE), and in determining which patients may benefit from penicillin skin testing, graded-dose challenge, or desensitization. Cross-reactivity between penicillin and other beta-lactams is less common than previously thought.