Signaling pathways play a critical role in the maintenance of cellular structure and function. These pathways can act together with synergistic or antagonistic outcome. Cooperative and integrative cellular communication networks, otherwise known as crosstalk can amplify signaling cascades. Here, we focus on receptor crosstalk in the context of cardiovascular pathologies, mainly involving the epidermal growth factor receptor (EGFR), a critical mediator of multiple receptor pathways in normal physiological and pathophysiological processes. Considerable experimental evidence suggests that the uncontrolled expression of EGFR contributes to tumorigenesis through inhibition of apoptosis, angiogenesis, anchorage-independent growth and tumor-associated inflammation. Abnormal activation of the intrinsic tyrosine kinase of EGFR through mutation or overexpression is observed in various human cancer types. On the other hand, the role of EGFR in vascular biology is not well understood. In cardiovascular pathologies, such as atherosclerosis and restenosis, vascular smooth muscle cells (SMCs) migrate and proliferate, contributing to neointima formation, whilst apoptosis may cause plaque instability. EGFR can be transactivated by numerous pathologic stimuli that regulate SMC behaviour. This review describes our current understanding of the role of EGFR in SMC biology and pathology.