Endothelial cells (EC) and vascular smooth muscle cells (VSMC) are the main cell types within the vasculature. We describe here how microRNAs (miRs)— noncoding RNAs that can regulate gene expression via translational repression and/ or post-transcriptional degradation—distinctively modulate EC and VSMC function in physiology and disease. In particular, the specifi c roles of miR-126 and miR- 143/145, master regulators of EC and VSMC function, respectively, are deeply explored. We also describe the mechanistic role of miRs in the regulation of the pathophysiology of key cardiovascular processes including angiogenesis, atherosclerosis, and in-stent restenosis post-angioplasty. Drawbacks of currently available therapeutic options are discussed, pointing at the challenges and potential clinical opportunities provided by miR-based treatments.