ZAP-70 is a 70 kD protein of tyrosine kinase found in T-cells and natural killer cells. ZAP-70 is useful for the identification of a subset of chronic lymphocytic leukemias (CLL). In CLL, the ZAP-70 expression is closely associated with an unmutated configuration of the immunoglobulin heavy-chain variable region (IgVH) genes. ZAP-70 expression is an excellent surrogate marker for the distinction between the Ig-mutated (ZAP-70 negative) and Ig-unmutated (ZAP-70 positive) CLL subtypes and can identify patient groups with divergent clinical courses. The ZAP-70 positive Ig-unmutated CLL cases have a poorer prognosis.