Several cell types have been suggested as giving rise to chronic lymphocytic leukemia (CLL), and these suggestions have reflected the sophistication of technology available at the time. Although there is no consensus as to the normal cellular counterpart(s) in the disease, an antigen-experienced B lymphocyte appears required based on surface membrane phenotypes and gene expression profiles. However, what is still unclear is whether a single or multiple normal precursors were stimulated to evolve into CLL and at what stage(s) this occurred. A unifying, parsimonious theory is that CLL clones with either mutated or unmutated IGHVs derive from marginal zone B cells. However, evidence for remarkably similar B-cell receptor amino acid sequence and striking differences in polyantigen and autoantigen-binding activity, found in some but not all CLL clones, challenge a single-cell derivation for CLL. In this Perspective, we summarize data regarding normal counterparts of CLL cells and suggest that a multistep process of leukemogenesis is important to consider when assigning a cellular origin for this disease. Finally, although available data do not definitively identify the cell(s) of origin, we offer possibilities for single- and multiple-cell origin models as straw men that can be improved on and hopefully lead to final answers to this puzzle.