AbstractAdenosine deaminases acting on RNA (ADARs) convert adenosines to inosines in double‐stranded RNA in animals. Identification of more ADAR targets and genome sequences of diverse eukaryotes present an opportunity to elucidate the origin and evolution of ADAR‐mediated RNA editing. Comparative analysis of the adenosine deaminase family indicates that the first ADAR might have evolved from adenosine deaminases acting on tRNAs after the split of protozoa and metazoa. ADAR1 and ADAR2 arose by gene duplications in early metazoan evolution, ∼700 million years ago, while ADAR3 and TENR might originate after Urochordata–Vertebrata divergence. More ADAR or ADAR‐like genes emerged in some animals (e.g., fish). Considering the constrained structure, ADAR targets are proposed to have evolved from transposable elements and repeats, random selection, and fixation, and intermolecular pairs of sense and antisense RNA. In some degree, increased ADAR‐mediated gene regulation should substantially contribute to the emergence and evolution of complex metazoans, particularly the nervous system. © 2009 IUBMB IUBMB Life, 61(6): 572–578, 2009