Antihistamines are the cornerstone of allergy therapy and are not expected to cause hypersensitivity reactions. We describe two cases, one had urticaria to multiple anti-H1-preparations and the other had anaphylaxis to hydroxyzine. We also provide a review of the English literature on reported reactions regarding causative preparations and manifestations. The latter showed a wide range; most commonly urticaria/angioedema, contact dermatitis, anaphylaxis, and fixed drug eruption (FDE). Most reported cases were young to middle age adults, with apparent predilection to female subjects. The onset of reactions varied from a few minutes for anaphylaxis and urticaria/angioedema, several hours for maculopapular rashes, or longer for contact dermatitis and FDE. Almost all antihistamines have been reported as causing reactions; cetirizine was the most common oral preparation followed by its parent drug, hydroxyzine. Doxepin cream was the most commonly implicated topical preparation in causing contact dermatitis. A causal relationship is often difficult to recognize because the reaction may be similar to the disease being treated with that antihistamine preparation. Reactions to one preparation are likely to occur, but not always, to other members of the same class. Diagnosis is based on clinical suspicion and may be verified by challenge testing. Except for patch testing in contact dermatitis or fixed eruption, other tests have not shown optimal reliability. In most cases, challenge testing with multiple preparations would identify one or more preparations that can be tolerated. Although hypersensitivity to antihistamines seems to be very rare, awareness of the problem would reduce its misdiagnosis.