An understanding of the molecular biology of B-cell chronic lymphocytic leukemia (B-CLL) has led to the appreciation that several different B-cell diseases are represented under this name. Variability in the bcl-2 family of proteins, p53 mutation, or the presence of various chromosomal abnormalities corresponds to variability of the clinical course of disease and response to therapy. Differential expression of cell surface adhesion molecules by B-CLL cells have also been shown to influence clinical outcome, as have the expression of immune regulatory molecules (eg, CD80, CD40R, CD27 and CD79b). Recent work studying immunoglobulin-heavy chain gene rearrangement postulates at least two subsets of B-CLL originating from different stages of B-cell development and following different clinical courses. The knowledge that B-CLL is the final consequence of many different molecular perturbations may allow the development of chemotherapies, immunotherapies, and gene therapies that target the specific molecular defect in a given case of B-CLL.