Research in chronic lymphocytic leukemia (CLL) has undergone a resurgence of interest in the last decade. While it is obvious that most patients with CLL have typical mature B cells, a number of variants such as splenic lymphoma villous lymphocytes, mantle cell leukemia, and prolymphocytic leukemia need to be considered in the differential diagnosis. This can be established by immunophenotype studies and morphology. Cytogenetic abnormalities are emerging as being of interest, with abnormalities in chromosomes 11 and 17 having major prognostic significance. Immune disregulation is complicated in that along with hypergammaglobulinemia and T-cell dysfunction, the emergence of antibodies directed against hematopoietic cells causes autoimmune hemolytic anemia, neutropenia, and thrombocytopenia. A number of prognostic factors are emerging as being more influential in prognosis and stage, such as serum beta2-microglobulin and soluble CD23. Apoptosis dysregulation is a major feature of CLL, and while no clear pattern has emerged, abnormal levels of bcl2 are common in CLL and bcl2 to bax ratios are also commonly disturbed. Bcl1 levels are commonly increased. Treatment has changed radically. The purine analogs have been demonstrated to be the most active group of drugs in CLL. Combinations of purine analogs, such a fludarabine or 2-chlorodeoxyadenosine, with alkylating agents are emerging as new treatments. The most recent development has been the emergence of two monoclonal antibodies, rituximab (Rituxan; IDEC Pharmaceuticals, San Diego, CA, and Genentech, Inc, San Francisco, CA; directed against CD20) and Campath-1H (directed against CD52 in CLL). The activity of rituximab in lymphoma has been less prominent in small lymphocytic lymphoma (the lymphomatous counterpart of CLL) and this has led to dose escalation studies in CLL with a good level of response. Campath-1H is emerging as another major antibody with marked effect against disease, particularly in the blood and bone marrow. Autologous, allogeneic, and mini-transplant are also being explored extensively. The prognosis for patients with CLL is changing as these new treatments become available.