The zeta chain is a 16-kDa molecule associated with the T-cell receptor (TCR)-CD3 complex in T lymphocytes and FcgammaRIII in CD3(-)CD56(+)CD16(+) natural killer (NK cells). The zeta chain functions as a transmembrane signaling molecule in lymphocytes. Expression of zeta was found to be decreased in CD4(+) and CD8(+) T lymphocytes isolated from the tumor site or from the peripheral circulation of patients with cancer. A quantitative flow cytometry-based assay for zeta-chain expression allows for reproducible serial evaluations of disease- or therapy-associated changes in expression of this signaling molecule in phenotypically defined subsets of immune cells. Semiquantitative evaluation of zeta expression in paraffin-embedded tissue specimens can link it to the conventional markers of prognosis or survival. Several distinct mechanisms may be responsible for decreased/absent zeta in T cells of patients with cancer. Monitoring for zeta expression is useful for assessing immune competence in these patients and for following changes in immune competence during anticancer therapies. Correlations made between clinical findings, pathologic results, and zeta expression in immune cells suggest that low/absent zeta is predictive of poor prognosis and survival in patients with cancer. Thus, zeta is emerging as a clinically relevant signaling molecule, which also seems to predict a favorable response to biologic therapies and could be helpful in a selection of patients for immunotherapy trials. Validation studies have yet to be performed for this putative immunologic biomarker. Its consistent use for monitoring under standardized conditions of cancer patients treated with biotherapies may help in confirming a role for zeta as a correlate of prognosis or survival.