Identifying and characterizing the earliest stages of disease is particularly important in disorders such as Chronic Lymphocytic Leukemia (CLL), where the initiating oncogenic events are unknown. Improvements in diagnostic technology have led to the detection of disease-associated markers in increasing numbers of otherwise healthy individuals. However, many of these approaches do not necessarily constitute evidence of a neoplastic process: the identification of a disease-precursor state requires evidence at several levels. The advent of high-sensitivity flow cytometry techniques, developed to monitor disease in CLL patients undergoing treatment, has allowed accurate enumeration of sub-clinical levels of monoclonal B-cells with a CLL phenotype in healthy individuals from the general population and CLL families. The age and gender distribution parallels that of clinical disease. Emerging evidence confirms the association between the aberrant cells in healthy individuals and those in CLL patients at the phenotypic, genotypic and clinical level, particularly in families with inherited susceptibility. These cells provide a tool for studying the events responsible for disease initiation.