Ankyrins are a ubiquitously expressed family of membrane-adaptor proteins found in most vertebrate tissues. Since the first ankyrin polypeptide was identified over 25 years ago (1), studies in humans, mice, and lower organisms have implicated critical roles for ankyrins in normal metazoan physiology. This review will provide an overview of the ankyrin family and highlight seminal findings in the field which have linked dysfunction in ankyrin-based pathways with defects in metazoan physiology and human disease.