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The division of CLL into 2 broad subsets with highly significant differences in clinical behavior was reported in 2 landmark papers in Blood in 1999.1,2 The simple analysis of the mutational status of the IGV regions provided both a prognostic indicator and an insight into the cellular origins. Derivation from B cells with very low or no IGV mutations generally leads to a more aggressive disease course than derivation from B cells with higher levels. This finding focused attention on surface Ig (sIg), the major B-cell receptor, and revealed dynamic antigen engagement in vivo as a tumor driver. It has also led to new drugs aimed at components of the intracellular activation cascades. After 20 years, the 2 senior authors of those papers have looked at the history of the observations and at the increasing understanding of the role of sIg in CLL that have emanated from them. As in the past, studies of CLL have provided a link between biology and the clinic, enabling more precise targeting which attacks critical pathways but minimizes side effects.