Monoclonal B-cell lymphocytosis (MBL) is defined as a clonal B-cell expansion whereby the B-cell count is less than 5 × 10⁹/L and no symptoms or signs of lymphoproliferative disorders are detected. Based on B-cell count, MBL is further divided into low-count and clinical MBL. While low-count MBL seems to carry relevance mostly from an immunological perspective, clinical MBL and chronic lymphocytic leukemia appear to be overlapping entities. Only a deeper knowledge of molecular pathways and microenvironmental influences involved in disease evolution will help to solve the main clinical issue, i.e. how to differentiate nonprogressive and progressive cases requiring intensive follow-up.