Vascular dysfunction is the underlying cause of nearly 80% of heart disease cases, and its initiation and progression can be exacerbated by circulating factors, such as IGF-1 (insulin-like growth factor 1). IGF-1, which is highly homologous with insulin, elicits a response via a classical tyrosine kinase receptor, the IGF-1R (IGF-1 receptor). However, it has been suggested that the IGF-1R may also be coupled to a heterotrimeric G-protein and can thus modulate cellular processes via this alternate pathway. The objective of the present study was to investigate the structural aspects of IGF-1R coupling to a heterotrimeric G-protein in VSMCs [vascular SMCs (smooth muscle cells)], as well as examine the contribution of this pathway to cellular responses that are related to vascular disease. We found that the intracellular subunit of the IGF-1R precipitates with two G-protein subunits. The G(βγ)-mediated pathway contributes to both proliferation and migration. We also show that IGF-1 specifically activates G(αi) and can directly interact with both G(αi1) and G(αi2). A phospho-screen using a novel specific G(αi)-peptide inhibitor reveals a number of potential downstream effectors of this pathway, although our results show that it is not essential for SMC proliferation or migration.