The Epidermal Growth factor receptor (EGFR) is a receptor tyrosine kinase involved in the regulation of cell proliferation, survival and differentiation. Pathophysiological effects of EGFR include parainflammatory dysregulation of tissue homeostasis leading for example to vascular dysfunction and fibrosis. In addition to ligand binding, activation of EGFR signalling can be induced by transactivation e.g. via ligands of G-protein coupled receptors (endothelin receptor type A, ET_A; purinergic receptors, P2YR; a₁-adrenergic receptors, a₁-AR) or reactive oxygen species, a mechanism proposed to contribute significantly to ERK1/2-activation and pathological phenotypes in vascular smooth muscle cells (VSMC). We investigated the importance of EGFR in primary VSMC from aorta of mice with targeted deletion of the EGFR (EGFR^D/DVSMCand EGFR^D/+VSMC) and the respective littermate controls (EGFR^+/+VSMC) with respect to ERK1/2-phosphorylation and Ca²⁺-homeostasis. In EGFR^D/DVSMC EGF-induced signalling (ERK1/2-activation and Ca²⁺-homeostasis) was abolished. In EGFR^D/DVSMC or EGFR^D/+VSMC, endothelin-1(ET-1)-induced ERK1/2-activation and responsivity with respect to Ca²⁺ was significantly reduced. The same holds true in EGFR^D/DVSMC for a₁-AR stimulation by phenylephrine (PE). Reactive oxygen species stress, imposed by addition of H₂O₂, induced ERK1/2-activation in EGFR^+/+VSMC and EGFR^D/+VSMC but not in EGFR^D/DVSMC, whereas responsivity with respect to Ca²⁺ was not reduced. The same holds true for purinergic stimulation by ATP. In conclusion, EGFR is important for basal VSMC homeostasis and ERK1/2-activation by the tested GPCR or radical stress. Ca²⁺-signaling is modulated by EGFR differentially with respect to the fraction of responders and magnitude of the signal. Thus, EGFR seems to be Janus-faced for VSMC biology.