Cardioprotection is a promising novel therapeutic approach for the treatment of ischemic heart disease (IHD). Various cardioprotective methods such as ischemic, anesthetic and G-protein-coupled-receptor (GPCR) based preconditioning have been shown to be reliant on the presence of unique regions in the sarcolemma termed caveolae. Caveolae compartmentalize and concentrate various classes of signaling molecules involved in stress-resistance, including important mediators of cardioprotection such as receptor tyrosine kinases, GPCRs and their subunits. The unique morphology of caveolae arises from the expression of its coat proteins belonging to those of caveolin, cavin and Popeye domain-containing (Popdc) family of proteins. As outlined in this review, although contributions of caveolins (especially Caveolin-3) in cardioprotection are relatively well-characterized, recent studies indicate that members of the cavins and the Popdc family of proteins are also crucial for sarcolemmal caveolae formation, an important determinant of ischemia-reperfusion (I-R) injury. In this article, we discuss the evidence for the involvement of caveolins, cavins and Popdc family of proteins in cardioprotective signaling and the essential role of caveolae in age-related reduction of cardioprotective signaling. Age-related changes in sarcolemmal makeup as evidenced by down-regulation of caveolins in several types of tissues is linked to decreased stress-resistance, and may help partially explain the refractoriness to protective stimuli in the aging heart. Hence, a greater understanding of the role of caveolae and its coat proteins as brieﬂy outlined here may help facilitate the development of cardioprotective strategies as despite the decades of research, currently there are no effective treatments for limiting I-R injury. Since many of the existing experimental cardioprotective interventions such as the clinically feasible post-conditioning method is reliant on caveolae, methods that enhance or restore caveolae in the aged heart may be a viable therapeutic strategy for the treatment ischemic heart disease.