Activation of the endothelin A receptor (ET(A)) by endothelin-1 (ET-1) mediates events that regulate mitogenesis, apoptosis, angiogenesis and metastasis in tumours. Specific blockade of ET(A) may have anticancer effects, while retaining beneficial endothelin B receptor (ET(B))-mediated effects such as apoptosis and clearance of ET-1. ZD4054 is an orally active, specific ET(A) antagonist in clinical development. In receptor-binding studies, ZD4054 specifically bound to ET(A) with high affinity; no binding was detected at ET(B). In a randomised placebo-controlled trial in eight healthy volunteers, a single oral dose of ZD4054 reduced forearm vasoconstriction in response to brachial artery infusion of ET-1, thus providing clinical evidence of ET(A) blockade. ET(B) blockade was assessed in an ascending, single-dose, placebo-controlled trial in 28 volunteers. For all doses of ZD4054, mean plasma ET-1 concentrations measured at 4 and 24 h were within the placebo reference range (a rise in ET-1 would indicate ET(B) blockade) and there was no evidence of dose-related changes. These data confirm the specificity of ZD4054 for ET(A), with no activity at ET(B) in a clinical or preclinical setting. As a result of this specificity, ZD4054 has the potential to block multiple ET(A)-induced pathological processes, while allowing beneficial ET(B)-mediated processes to continue, which may, in turn, lead to an effective cancer therapy.