Chronic lymphocytic leukemia (CLL) is characterized by the monoclonal expansion of small mature-looking B cells that accumulate in the blood, marrow, and lymphoid organs, and have a remarkable phenotypic homogeneity. By definition, CLL cells co-express CD5 and CD23 with faint to undetectable amounts of monoclonal surface immunoglobulins (sIg). The concept of phenotypic homogeneity has been reinforced by gene expression profiling data, which suggest that the pathogenesis of CLL has to be associated with a fairly common mechanism of transformation. In recent years the biology of CLL has been enriched by an unprecedented flurry of new observations that are leading to a better understanding of the natural history of the disease. Still CLL cells have so far defied any attempt to satisfactorily answer the simple time-honored question of what their cell of origin is. It is the purpose of this review to discuss the features a cell must possess to be considered with reasonable approximation the normal counterpart of a CLL B cell.