Somatic hypermutation fine tunes the antigen-binding site and influences the level of epitope specificity in CLL. Seiler et al report that M-CLL mAbs recognized multiple peptides that shared well-defined amino acid motifs, whereas U-CLL mAbs bound a series of peptides of quite dissimilar sequence. From the mAbs side, U-CLL mAbs were promiscuous, whereas M-CLL mAbs were far more selective and specific. Assuming that stimulation through the BCR triggers proliferation of the CLL clone, the implication from these findings is that somatic hypermutation induces conformational changes that restrict the antigen-binding range, thus limiting the chances of receiving stimulatory signals.