Clinicians should be familiar with which antibiotics are safe to use for different types of penicillin-allergic reactions. Clinically, it is convenient to divide patients with penicillin allergy into three categories: those with unknown or possible reactions to penicillin, those with a drug fever or rash, and those with hives or anaphylactic reactions. Beta-lactam antibiotics may be used safely for patients with unknown/possible penicillin allergy and drug fever or rash. Penicillins or beta-lactams should not be used for patients with hives or anaphylactic reactions. For all patients, clinicians should consider antimicrobial therapy with an antibiotic that does not cross-react with penicillins or beta-lactams. This article reviews how clinicians should select antimicrobials in penicillin-allergic patients.