Abstract Advances in our understanding of normal B-cell differentiation have allowed for improved classification and therapy of B-cell malignancies. B-cell neoplastic diseases may be classified more accurately according to the differentiation stages of presumed normal B-cell counterparts. These advances have challenged the notion that chronic lymphocytic leukemia represents a malignancy of naive CD5 B cells. Analyses of immunoglobulin genes and gene expression patterns through microarray have defined at least two types of chronic lymphocytic leukemia that differ in their tendency toward disease progression. Nevertheless, these types still share more in common than they do with other lymphoid malignancies, and both may be derived from memory-type B cells. Advances in immune therapy are revolutionizing the approach to therapy. B-cell surface differentiation antigens constitute tissue-specific targets for passive immune therapy. Since the US Food and Drug Administration approval of rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA) for use in the treatment of follicular lymphoma, monoclonal antibody therapy is being considered for all types of B-cell malignancies. The ability to transform leukemia and lymphoma B cells into effective antigen-presenting cells through CD40 ligation allows for autologous immune recognition of neoplastic cells. Together, active and passive immune approaches have potential for effective treatment of patients with these diseases. Semin Oncol 29 (suppl 2):98-104. Copyright © 2002 by W.B. Saunders Company.