Five new small cell carcinomas (SCC) cell lines and a large cell carcinoma (LCC) cell line were established from human lung cancers. The SCC cell lines had, as a group, common phenotypic properties which distinguished them from non-SCC cell lines. However, the studies also revealed a considerable biological heterogeneity among the individual SCC cell lines. Thus, the SCC cell lines had a typical growth pattern with cell clusters in suspension or partly adherent to the bottom. All the lines examined grew in agarose with variable cloning efficiencies, and all but one line formed tumors subcutaneously in nude mice. The ultrastructure of the SCC cell lines was characteristic with dense core granules at a variable frequency. Neuron-specific enolase was detectable in all SCC cell lines, usually in large amounts, and an inconstant production of a spectrum of polypeptide hormones was found, typical of SCC. The LCC cells proliferated in monolayers, formed colonies in agarose and grew in nude mice. Ultrastructurally, the LCC cell line differed from the SCC cell lines in having intra- and intercellular lumina and tonofilaments. The capacity of the LCC and a previously established squamous cell carcinoma cell line (U-1752) to produce neuron-specific enolase and polypeptide hormones was characteristically much lower than that of the SCC cell lines. We conclude from this study that SCC cell lines, although individually distinct from one another, are quite homogeneous as a group in expressing a set of basic common neuro-endocrine markers. However, these studies also suggest some biological relationship between SCC, LCC and SQC by virtue of their expression of some common neuro-endocrine markers, in support of the concept of a common histogenetic origin of human lung cancers.