The focus of this review is on the ankyrin gene family, key elements in the interaction of the spectrin-based membrane skeleton with the plasma membrane in a variety of tissues and multicellular organisms. The structure/function relationships of ankyrin molecules are reviewed, illustrating how these proteins are uniquely suited to serve as adaptors between the membrane skeleton and a number of integral membrane proteins. Advances in the understanding of ankyrin biology in the brain are discussed and used to show how ankyrins may be involved in the establishment and/or maintenance of specialized plasma membrane domains. Finally, recent research in hematological and neurological disorders are reviewed, suggesting that ankyrins have a role in the development of human disease.