Data are presented from two cell culture systems which support the notion that a multi-drug-resistant phenotype occurs in human tumor cell populations. Human small cell lung cancer cell lines derived from patients in relapse following intensive combination chemotherapy demonstrate broad cross-resistance to nine standard drugs in vitro. However, analysis of [14C]glucosamine-labeled glycoproteins in the small cell lung cancer cell lines failed to identify any consistent association between a specific glycoprotein marker and the drug-resistant phenotype. Evaluation of drug sensitivity of human tumor cells in primary culture (colony-forming assay) has indicated that multidrug-resistant cells may be present in tumor cell populations even in the absence of prior drug therapy. Several features of the multidrug-resistant phenotype, as observed in these human tumor cell populations, differ from those observed in Chinese hamster cell systems. In particular, the variability in patterns of resistance to various agents and in expression of glycoprotein markers suggests that a substantial amount of genetic heterogeneity underlies this phenotype in human tumors.