Angiotensin II (Ang II) has been shown in several experimental conditions to stimulate the production of endothelin (ET), an endothelium-derived constricting factor. It is therefore not surprising that some of the physiological or pathological effects of angiotensin II are in fact mediated by endothelin through interaction with its specific receptors. For instance, ET receptor antagonists block part of the pressor effect of Ang II, especially when the treatment is initiated early. Accordingly, Ang II-induced vasoconstriction appears to be dependent on ET release, especially in smaller arteries. Moreover, blockade of ET receptors has a profound effect on Ang II-induced hypertrophic remodeling of small arteries. However, the contribution of ET appears to be limited to the initial phase of hypertrophy, as ET receptor antagonists do not regress already established vascular hypertrophy, but completely prevent it. Interestingly, ET also appears to mediate part of Ang II-induced vascular superoxide production in vivo. Thus, blocking ET receptors may provide similar cardiovascular benefits as inhibiting the renin-angiotensin-aldosterone system, and the combination of inhibitors of both systems therefore appears counter-intuitive. However, experimental data strongly support added benefits of a combined treatment. Therefore, the interaction between the renin-angiotensin system and ET may become clinically significant if clinical trials confirm the already available experimental data.