Multiple signaling pathways link the angiotensin II (Ang II) type 1 (AT₁) receptor to Gq-dependent inositol phosphate (IP) production and Gq-independent phospho-extracellular signal-activated kinase (p-ERK) 1/2 activation by Ang II in the regulation of cardiovascular vasoconstriction and cell growth, respectively. An Ang II analogue, [Sar¹, Ile⁴, Ile⁸]Ang II, did not stimulate Gq-dependent IP production, but still activated Gq-independent p-ERK1/2 in human coronary artery smooth muscle cells as well as in a cell line that stably expressed AT₁. This activation was mostly mediated by [Sar¹, Ile⁴, Ile⁸]Ang II-induced Gq-independent epidermal growth factor receptor transactivation. We found that AT₁ receptor signaling shows bifurcation into functionally separate pathways. A clear understanding of this unique signaling may be necessary for the development of therapeutic agents to treat disorders such as hypertension and cardiac hypertrophy. (Hypertens Res 2004; 27: 765-770)