-Ajigiotensin-converting enzyme (ACE, 1 IIEC 3.4. 15.1) is a zinc metalloprotease catalyzing the hydrolysis of carboxyterminal dipeptides from oligopeptidesubstrates, most notably the decapeptide angiotensin I (AI) and the nonapeptide bra-dykinin (BK)(Soffer, 1981). ACE is a component of the renin-angiotensin system (RAS), and in view of recent ad-vances in our understanding of the physiology and pathophysiology of the RAS (Campbell, 1987; Dzau, 1988), it is important that the implications of these new concepts are explored in terms of what is known about the biochemistry of ACE. Further, there has been a dramatic increase in the use of potent orally effective, active-site-directed ACE inhibitors (Johnston, 1988) in the absence of a complete un-derstanding of the molecular basis for their activity or of the full physiological significance of their use. The biochemical and enzymatic properties of ACE have recently been reviewed in extensive detail (Soffer, 1976, 1981; Ondetti & Cushman, 1982; Erdos, 1987; Ehlers & Riordan, 1989) and need not be reiterated here. However, a perspective in terms of the role of ACE, both within and independent of the framework of the RAS, would appear to be both timely and useful. Although ACE was discovered in 1954 (Skeggs et al., 1954), more than a decade elapsed before it became clear that ACE plays a critical role inthe RAS, after the finding that the most important site for the generation of circulating All was the lungs (Ng & Vane, 1967, 1968). In thisorgan ACE is both abundant (Cushman & Cheung, 1971; Lieberman & Sastre, 1983) and uniquely positioned to act on circulating substrates by its localization on the luminal surface of endothelialcell plasma membranes in the lung’s rich vasculature (Ryan et al., 1975; Caldwell et al., 1976; Wigger & Stalcup, 1978). ACE was therefore incorporated into the central dogma of the