Considerable data indicate that lipid (membrane) rafts and caveolae (caveolin-containing rafts) play critical roles in the regulation of a wide variety of cardiovascular cells, including vascular endothelial and smooth muscle cells and cardiac myocytes and fibroblasts. The contribution of rafts/caveolae to normal function includes providing a portal for entry of nutrients and a cellular exit site for certain entities (such as atrial natriuretic peptide in the heart) and as sites that concentrate signal transduction molecules, thereby serving as cellular loci for numerous types of signaling. Endothelial nitric oxide synthase (eNOS) has been the most extensively studied caveolae-localized signaling entity that is important for cardiovascular function. Many G-protein-coupled receptors (GPCRs), the largest receptor family in the human and other mammalian genomes, localize to caveolae. Some GPCRs localize to caveolae prior to exposure to their cognate agonists but other GPCRs translocate to caveolae following interaction with agonists; in some cases, caveolae are sites for internalization of GPCRs. Caveolae may also help limit “basal” levels of signal transduction. A role for caveolins and caveolae has been implicated in the pathophysiology of numerous cardiovascular disorders. Such disease settings include myocardial ischemia and ischemia/reperfusion (in which disruption of caveolae decreases the protection of cells and tissues from damage by hypoxia/reperfusion) and in patients with idiopathic pulmonary hypertension (whose pulmonary arterial smooth muscle cells show increased expression of caveolins and caveolae). Therapies that target caveolins and caveolae thus have the potential to provide novel approaches for the treatment of a variety of cardiovascular disorders by altering functional activities, including signal transduction by GPCRs.