Intracellular signal transduction events are precisely regulated in space and time. This is achieved in part by A-Kinase Anchoring Proteins (AKAPs) that tether signaling enzymes such as protein kinases and phosphatases in proximity to selected substrates. AKAP targeting provides an efficient means to reversibly control the phosphorylation status of key substrates and contributes to the dynamic regulation of sophisticated cellular events. Using a variety of genetic, electrophysiological and live-cell imaging techniques we show that AKAPs, which enhance the precision of signaling events, are up-regulated under certain pathophysiological states. This leads to aberrant regulation of certain physiological processes and disorders such as diabetes and heart disease.