The intracellular parent of the cysteinyl leukotrienes (cysLTs), leukotriene (LT) C₄, is formed by conjugation of LTA₄ and reduced glutathione by LTC₄ synthase in mast cells, eosinophils, basophils, and macrophages. After extracellular export, LTC₄ is converted to LTD₄ and LTE₄ through sequential enzymatic removal of glutamic acid and then glycine. Only LTE₄ is sufficiently stable to be prominent in biologic fluids, such as urine or bronchoalveolar lavage fluid, of asthmatic individuals and at sites of inflammation in animal models. LTE₄ has received little attention because it binds poorly to the classical type 1 and 2 cysLT receptors and is much less active on normal airways than LTC₄ or LTD₄. However, early studies indicated that LTE₄ caused skin swelling in human subjects as potently as LTC₄ and LTD₄, that airways of asthmatic subjects (particularly those that were aspirin sensitive) were selectively hyperresponsive to LTE₄, and that a potential distinct LTE₄ receptor was present in guinea pig trachea. Recent studies have begun to uncover receptors selective for LTE₄: P2Y₁₂, an adenosine diphosphate receptor, and CysLT_ER, which was observed functionally in the skin of mice lacking the type 1 and 2 cysLT receptors. These findings prompt a renewed focus on LTE₄ receptors as therapeutic targets that are not currently addressed by available receptor antagonists.