OBJECTIVE To review the pharmacology, pharmacokinetics, clinical efficacy, and adverse effects of zafirlukast. Therapeutic issues regarding the use of a leukotriene-receptor antagonist as prophylactic antiinflammatory therapy for asthma are also discussed. METHODS A MEDLINE search was conducted to identify pertinent literature, including preclinical trials, clinical trials, and reviews. Pharmacokinetic and dosing information were abstracted from the product labeling. METHODS All available published articles describing double-blind, placebo-controlled trials of both oral and aerosol zafirlukast in patients with asthma or rhinitis were reviewed. These included single-dose studies with zafirlukast against exercise, allergen, leukotriene D4 (LTD4), and platelet-activating factor (PAF) challenges, and 6- and 13-week trials in patients with asthma. Studies describing clinical trials with long-term use or comparisons with other asthma medications as reported in abstracts are also included. METHODS Information on the safety and efficacy of zafirlukast from single- and multiple-dose studies was evaluated on the basis of statistical significance relative to placebo treatment. RESULTS Zafirlukast, a potent and selective antagonist of the cysteinyl leukotriene receptor, blocks leukotriene-mediated pathologic events in both experimental animal and clinical disease models. Zafirlukast antagonizes LTD4-, PAF-, and exercise-induced bronchoconstriction, and blocks both early- and late-phase responses following allergen provocation in patients with atopic asthma. Greater efficacy is noted following oral administration than with aerosol dosing, presumably because of the enhanced delivery of drug when ingested rather than inhaled. CONCLUSIONS Zafirlukast is the first orally active leukotriene-receptor antagonist approved by the Food and Drug Administration for the prophylactic and chronic treatment of asthma. Since the leukotrienes play an important role in the underlying inflammatory processes of asthma, zafirlukast represents a new antiinflammatory option available in an oral dosage form. It is clear that this agent has therapeutic activity in patients with asthma, but its effectiveness relative to other antiasthma medications still needs confirmation. Data from clinical studies support the use of zafirlukast as first-line therapy in patients with mild-to-moderate asthma. Further research is needed to establish its role as an add-on agent for patients with severe asthma, aspirin-sensitive asthma, and both allergies and asthma. In addition to having a favorable safety and efficacy profile, zafirlukast has the advantage of being an oral agent with twice-daily dosing; these attributes offer the potential for greater patient adherence to pharmacotherapy and, thereby, improved control of asthma symptoms.