Progastrin-releasing peptide (ProGRP) is a recently identified biomarker of small cell lung cancer (SCLC), a disorder of neuroendocrine tissue differentiation. The upper normal limit of ProGRP in the circulation is 50 pg/ml. Impaired glomerular filtration tends to increase circulating levels and confound the tumor marker significance of modestly elevated values. Excluding patients with renal failure, circulating levels did not exceed 80 pg/ml in benign disease (3% of cases in excess of the upper normal limit) or 120 pg/ml in malignancy other than lung cancer and neuroendocrine tumors (5% of cases in excess of the upper limit). ProGRP serum levels are clearly related to the lung cancer histological type with significantly higher levels observed in SCLC than in nonsmall cell lung cancer (NSCLC). Circulating ProGRP in excess of 120 mg/ml was found in only 4% of cases of NSCLC with another 22% presenting with modestly elevated levels in excess of the upper normal limit. By contrast, abnormal ProGRP results are found in 60-70% and in 75-90% of SCLC patients with local and extensive disease, respectively. ProGRP is a more sensitive biomarker than is neuron-specific enolase (NSE) for SCLC, but thus far has not been found in multivariate analysis to have independent prognostic significance. Preliminary studies suggest ProGRP will have utility in conjunction with NSE in monitoring the therapy of established SCLC.