Drug allergy describes clinical adverse reactions that are proved or presumed to be immunologically based. Allergic drug reactions do not resemble pharmacologic actions of the incriminated drug and may occur at fractions of what would be the therapeutic dosage. Allergic drug reactions are unpredictable; nevertheless, there is increased risk of drug hypersensitivity in (1) patients with cystic fibrosis who receive antibiotics; (2) patients with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) who receive trimethoprim-sulfamethoxazole or if human leukocyte antigen (HLA)-B*5701+ and receive the antiretroviral agent abacavir; (3) other genetically susceptible populations, e.g., Han-Chinese with HLA-B*1502+ who develop Stevens-Johnson syndrome and toxic epidermal necrolysis from carbamazepine, with HLA-B*5801+ who are at increased risk for such reactions from allopurinol, those with HLA-A*32:01 and receive vancomycin and develop drug reaction with eosinophilia and systemic symptoms syndrome; and (4) patients with a history of compatible allergic reactions to the same medication, similar class, or potentially unrelated medication. Specific patient groups at higher risk for drug allergy include patients with Epstein-Barr virus infection, chronic lymphatic leukemia, HIV/AIDS, cystic fibrosis, patients with seizures who are being treated with anti-epileptic medications, and patients with asthma (especially severe asthma) who are at increased risk of anaphylaxis from any cause, including drugs, compared with patients without asthma. In patients with a history of penicillin allergy, skin testing helps clarify the current level of risk for anaphylaxis by using the major (penicilloyl polylysine) and minor penicillin determinants in which sensitivity is 99%. If penicilloyl polylysine and penicillin G are used for skin testing, then the sensitivity is approximately 85-95%. When skin test results are negative, graded challenges are performed to administer optimal or truly essential antibiotics.