The role of inherited genetic factors in the etiology of chronic lymphocytic leukemia (CLL) and other B-cell lymphoproliferative disorders is now well established. Significant familial aggregation of CLL and B-cell lymphoproliferative disorders has been demonstrated, but the mode of inheritance is unknown. Identification of genes that when mutated confer an increased risk of these diseases is of immediate clinical relevance because it may offer clues to pathogenesis and highlight possible therapeutic targets. Furthermore, identification of these genes provides a greater understanding of the mechanisms of B-cell tumorigenesis in general. This article reviews current knowledge relating to inherited susceptibility to CLL and strategies that are being used to identify disease-causing mutations.