JRAAS 2001;2:219-26 Introduction The importance of the renin-angiotensin system (RAS) was first recognised in 1934. Extensive research started in the mid-1950s by Skeggs and co-workers,who identified the transformation of a decapeptide into an octapeptide by a factor from horse blood plasma. At that time, the two peptides were called hypertensin I and hypertensin II. In the same year, the laboratory synthesis of the octapeptide was reported by Bumpus et al. who named the peptide angiotonin. Soon, researchers made a compromise and the peptides were called angiotensin I (Ang I) and angiotensin II (Ang II). For a long period, the RAS was primarily viewed as a circulating endocrine system, in which renin, released by the kidney, cleaves angiotensinogen, produced by the liver, into Ang I. Ang I is converted to Ang II by angiotensin-converting enzyme (ACE),on passage through the pulmonary vasculature. However, it was then observed that levels of Ang II in the venous compartment were much higher than those shown in clearance studies, and also that renin isoforms were found outside the kidney. Thus,Ang II might be synthesised in various tissues, either from local sources or from components derived from the circulation.Local Ang II production was found to correlate with the patho-physiological status in rat myocardial infarction, and high levels of locallyproduced Ang II were accompanied by cardiac hypertrophy in mice. These findings have further evolved in the past decade, leading to the concept of the local RAS as a determinant of progression of organ failure. Today, the important question is whether the concept of the local RAS should be taken a step further. There is accumulating evidence that, in addition to the plasma membrane-localised RAS, various cell-types are responsive to the intracellular application of Ang II.The first published effect of intracellularly-applied Ang II was from De Mello, who showed that intracellular injection of Ang II is accompanied by a decrease in cellular junction conductance. This, and other observations,suggest the existence of an intracellular RAS. The purpose of this review is to examine whether the intracellular system is a myth, or should be acknowledged as a new entity, complementing the circulating and/or local RAS. To this end, we summarise the limited evidence for the presence of Ang II within the cell, and discuss the possible origin of intracellular Ang II receptors. In the next section, data about their pharmacology are presented and compared with those of plasma membrane receptors. After that, we review the effects on intracellular Ca ([Ca]i), representing the major signal transduction pathway modulated by intracellular Ang II.As a consequence of these changes in [Ca]i, intracellular Ang II induces effects such as vascular smooth muscle contraction, as well as cell growth. Although effects of intracellularly-applied Ang II are similar to the effects obtained after plasma membrane AT1receptor stimulation, they are insensitive to current therapeutic antagonistic agents.The latter finding indicates that understanding the pathophysiological importance of the RAS warrants an extensive investigation of intracellular Ang II effects.