The origin of antibody diversity has intrigued scientists for nearly a century. We now know that the diversity is achieved through a 2‐stage process. Gene rearrangement (catalyzed by the RAG1/2 recombinase) allows the production of a primary repertoire of antibodies; targeted deamination of cytosines within these rearranged antibody genes (catalyzed by the DNA deaminase AID) then allows them to be further diversified and matured by somatic hypermutation, gene conversion, and class‐switch recombination. Here we review the history of the uncovering of some of these processes, contrasting the relative importance of hypothesis and methodological developments in driving the research at different periods of the work.—Ganesh, K., Neuberger, M. S. Unraveling the roles of gene rearrangement and targeted deanimation in antibody gene diversification. FASEB J. 25, 1123–1132 (2011). www.fasebj.org