We compared and contrasted intracranial (i.c.) and subcutaneous (s.c.) heterotransplantation of small-cell carcinoma of the lung (SCCL) into athymic nude mice. Fresh human SCCL tumor specimens, tumor colonies grown in soft agarose and continuous cell lines were used. Tumors induced by the three types of specimens were similar, but s.c. and i.c. transplants differed. S.c. tumors had longer latent times, were non-invasive and non-lethal. I.c. tumors has shorter latent periods, invariably grew in the meninges, frequently invaded and destroyed the underlying brain, and were lethal. The tumor-inducing dose for i.c. transplantation was 10 to 1,000 times lower than for s.c. transplantation. Pooled colonies of SCCL tumor specimens grown in soft agarose were inoculated i.c. While they contained relatively small numbers of cells (400-10,000), 83% of these colony specimens induced tumors after 58-243 days, confirming the "stem-cell" origin of the colonies. I.c. and s.c. transplants retained the characteristic morphology of SCCL, and, with one exception, did not metastasize to distant organs. Continuous cell lines could be established readily from both types of transplants, and they retained the characteristic cytology, growth and biochemical properties of the original SCCL tumors. I.c. heterotransplantation of SCCL is a useful tool, especially when small numbers of tumor cells are available, and may provide a model to study the biology and therapy of meningeal carcinomatosis.