In addition to the important observations relating immunoglobulin (Ig) mutation status to clinical behavior, studies on the Ig expressed in chronic lymphocytic leukemia (CLL) have revealed compelling evidence that antigen selection contributes to the pathogenesis of this disease. CLL cells that use unmutated Ig can generally be distinguished from CLL cells that use Ig with somatic mutations by expression of the 70-kD zeta-associated protein (ZAP-70). ZAP-70 apparently enhances the capacity of CLL cells to respond to antigen, and therefore might play a causal role in the relatively aggressive clinical behavior noted for patients who have CLL cells that use unmutated Ig. Clinical surveys have found that expression of ZAP-70 by CLL cells is apparently a stronger predictor of early disease progression than is the use by CLL cells of unmutated Ig. As such, strategies that respectively monitor or target Ig-receptor signaling in CLL might be very useful in the risk assessment or treatment of this disease.