Histamine plays a central role in allergic responses. Inhibition of the weal and flare response to histamine is a traditional pharmacodynamic tool to measure the activity of H1-receptor antagonists. The time course and duration of cutaneous weal and flare inhibition are often used as surrogate measures of clinical efficacy. Pharmacodynamic differences among antihistamines are often interpreted to indicate differences in clinical efficacy. A systematic review of literature from 1980 to 2006 regarding the histamine induced weal and flare was undertaken. Search terms included ‘histamine’, ‘skin test’, ‘weal’, ‘flare’, and ‘antihistamine’; retrieved articles were searched for relevant studies not identified initially. Data from human studies on the inhibition of the weal and flare by second-generation antihistamines were extracted and assessed. A literature search from 1980 to 2006 was undertaken for comparative studies of second-generation antihistamines in the clinical settings of allergic rhinitis (AR) and chronic idiopathic urticaria; data extracted from these studies underwent systematic review. Differences were noted among second-generation antihistamines in terms of their ability to inhibit the histamine-induced weal and flare. Corresponding differences in terms of clinical efficacy in AR and chronic urticaria were not identified following a systematic review. The reasons for the disconnect between pharmacodynamic effects and clinical efficacy may include differences between the route and concentration of histamine, the involvement of mediators other than histamine in the allergic response, and the short time course of pharmacodynamic studies. The histamine-induced weal and flare response is a pharmacodynamic test that should not be used to compare the clinical efficacy of different antihistamines, and is not an adequate alternative to clinical end-point assessments in AR or chronic idiopathic urticaria.