Ankyrins are a family of multivalent membrane-adaptor proteins first identified in the erythrocyte over 25 years ago as a link between the anion exchanger and the spectrin-based cytoskeleton. Since their initial discovery, ankyrin function has been linked to protein targeting and membrane domain organization in a variety of cell types including erythrocytes, neurons, epithelial cells, and cardiomyocytes. Recent findings demonstrate that dysfunction in ankyrin-based cellular pathways in the heart leads to human ventricular arrhythmia and sudden cardiac death. This review will present an overview of the ankyrin family with special emphasis on the recently identified roles of ankyrin polypeptides in ion channel and transporter targeting in the heart.