Leukotriene (LT) E₄ mediates many of the principal features of bronchial asthma, such as bronchial constriction, hyperresponsiveness, eosinophilia, and increased vascular permeability. Furthermore, it is the most stable of the cysteinyl leukotrienes (CysLTs) and can be active at the site of release for a prolonged time after its synthesis. There might be several reasons why LTE₄ has been forgotten. LTE₄ demonstrated low affinity for CysLT₁ and CysLT₂ receptors in equilibrium competition assays. It was less potent than other CysLTs in functional assays, such as calcium flux, in cells transfected with CysLT₁ and CysLT₂. The introduction of CysLT₁ antagonists into clinical practice diverted interest into CysLT₁-related mechanisms, which were mediated mainly by LTD₄. However, experiments with animal models and human studies have revealed that LTE₄ has unique characteristics that cannot be explained by the current knowledge of CysLT₁ and CysLT₂. These activities include its potency relative to other CysLTs to increase airway responsiveness to histamine, to enhance eosinophilic recruitment, and to increase vascular permeability. Asthmatic airways also demonstrate marked in vivo relative hyperresponsiveness to LTE₄, especially in patients with aspirin-sensitive respiratory disease. This has stimulated a search for additional LT receptors that would respond preferentially to LTE₄ stimulation.