The identification of various signaling molecules found within caveolae and their functional interaction with the integral membrane protein caveolin, a major structural component of caveolae, suggests that these membrane microdomains participate in transmembrane signaling. Several lines of evidence indicate that caveolin may act as a scaffolding protein by direct interaction with and modulation of the activity of multiple signaling molecules. The compartmentation of various signaling molecules in caveolae and their direct and functional interaction with caveolin provides a paradigm by which these membrane microdomains are involved in regulating signal transduction pathways. By dysregulation of these signal transduction pathways caveolins may be involved in the pathogenesis of various diseases. This review focuses on the implications as well as controversies of the contribution of caveolae and caveolins for several human diseases and the potential implications to therapeutic strategies.