The significant correlation between disease aggressiveness and the gene and protein structures of the B-cell receptors (BCRs) expressed on chronic lymphocytic leukemia (CLL) cells, together with the evidence for chronic activation of the BCR pathway, have led to the hypothesis that this leukemia initiates and progresses by selecting normal B lymphocytes reactive with a restricted set of (auto)antigens. A study recently published in Nature identified a novel signal-initiating interaction between the third complementary determining region of the IG heavy chain variable domain (HCDR3) and an epitope in the second framework region (FR2) that appears to be unique to CLL B cells and that calls into question the need for classical antigen binding in the activation and expansion of the leukemic cells. These findings are discussed in the context of available information about the antigen reactivity of CLL B cells and its potential role in clonal survival and drive.