Several genetic abnormalities have been characterized in chronic lymphocytic leukemia (CLL) but these are predominantly secondary events and the initiating phenomena in the etiology of the disease are yet to be established. Studies of inherited susceptibility have identified the early oncogenic events in both familial and "sporadic" forms of several malignant disorders, and this may also be possible in CLL. However, the utility of linkage analysis in identifying a predisposition locus for the disease is limited because large multigenerational families segregating CLL are rare, while the more frequent small nuclear CLL families contain insufficient numbers of affected individuals. The power to detect predisposition gene(s) could be greatly increased by extending the number of affected individuals within a particular family, for example, by identifying family members with subclinical levels of disease. High-sensitivity flow cytometry techniques, developed to monitor disease in CLL patients undergoing treatment, have allowed accurate enumeration of subclinical levels of CLL cells in healthy individuals from the general population and CLL families. Emerging evidence confirms the phenotypic, genotypic, and clinical associations between the aberrant cells in healthy individuals and those in CLL patients. The data suggest that inherited factors increase the susceptibility to both indolent and aggressive CLL, and they provide unbiased demonstration that the age of onset in CLL families is younger than in the general population.