The pharmacology of salmeterol hydroxynaphthoate (SALM) has been investigated in respiratory tissues in vitro and in animal models in vivo. In guinea pig trachea and human bronchial smooth muscle, SALM was more potent than isoprenaline (ISO), salbutamol (SALB), and clenbuterol (CLEN). The duration of action was greater than 7 h, whereas that for ISO, SALB, and CLEN was 2, 11, and 45 min, respectively. The sustained activity of SALM was reversed by sotalol, but was reestablished when the beta-blocker was removed. SALM was greater than 3000-fold weaker than ISO in cardiac tissues, indicating high beta 2-adrenoceptor selectivity. In the conscious guinea pig, aerosolized SALM, SALB, and CLEN caused dose-related bronchodilatation. The activity of SALM persisted for at least 6 h, compared with less than 2 h for SALB and CLEN. SALM is also a potent inhibitor of mediator release from human lung, this effect being sustained for up to 20 hours. In guinea pig airways in vivo, SALM inhibited histamine-induced plasma protein extravasation for approximately 8 h. Salmeterol is a potent and selective beta 2-adrenoceptor agonist with a unique profile of action. It induces persistent bronchodilatation, sustained suppression of mediator release, and long-lasting inhibition of edema formation. This combination of properties may represent an important new advance in the treatment of bronchial asthma.