Publisher Summary Inflammatory mediators contribute to the pathophysiology of asthma and chronic obstructive pulmonary disease (COPD) suggesting that antagonists of mediator receptors or inhibitors of their synthesis would be beneficial in treatment. However, a large number of mediators are involved and many mediators share similar effects on the airways, inhibitors of single mediators may have had little or no clinical benefit to date. Anti-leukotrienes are mainly indicated for the treatment of asthma, and LTB4 inhibitors, such as LTB4 receptor antagonists, have no effect in asthma and are being considered for the treatment of COPD. Despite many years of continuing efforts by pharmaceutical companies, only one class of mediator antagonists, the anti-leukotrienes, has become established in the treatment of asthma, representing the first new class of therapy for asthma introduced in more than 40 years. So far, there has been no mediator antagonists introduced for the treatment of COPD. 5-lipoxigenase (5-LO) is a critical enzyme involved in the generation of leukotrienes. Inhibitors of 5-LO may be classified as direct inhibitors of the enzyme and indirect inhibitors that interfere with a nuclear membrane docking protein, 5-LO activating protein (FLAP) that is necessary for enzyme activation. Prostaglandin D2 (PGD2) is produced by activated mast cells and is a relatively selective marker for mast cells, and two G-protein-coupled receptors, DP1 and DP2 mediate many of its effects. Although thromboxane production is increased in asthma and thromboxane analogs are potent bronchoconstrictors in asthmatic patients, there is no convincing evidence that thromboxane receptor (TP) antagonists or thromboxane synthase inhibitors are effective in asthma. In addition to reviewing the antileukotrienes, the chapter also reviews other classes of mediator antagonists that have failed to show beneficial effects or those currently under-investigation.