An adriamycin-resistant cell line was established in culture by continuous exposure of SBC-3 cells, a cell line of human small-cell lung cancer, to increasing concentrations of adriamycin, followed by a cloning procedure. The resistant cells (SBC-3/ADM) were 30 times more resistant to the drug than the parent cells in terms of 70% lethal dose, determined by soft agar clonogenic assay. Uptake studies using [3H] daunomycin, which was completely cross-resistant to adriamycin, showed decreased influx and enhanced efflux of the agent. This resistance to adriamycin may be attributed to an alteration in membrane transport, resulting in reduced intracellular accumulation of the drug. Using the SBC-3/ADM cells, the activity of a variety of drugs was analyzed by soft agar clonogenic assay in order to search for a means of circumventing drug resistance. The SBC-3/ADM cells were markedly resistant to anthracycline antibiotics such as THP-adriamycin and 4'-epi-adriamycin. The cells were also resistant to structurally or pharmacodynamically unrelated compounds such as vincristine, mitomycin C, 40497S, an active compound of ifosfamide, and etoposide. However, the cells were as sensitive to mitoxantrone as the parent cells, and were considerably susceptible to cisplatin. These results suggest that mitoxantrone and cisplatin may exert a sufficient degree of activity for use against small-cell lung cancer resistant to adriamycin.