One of the problems in the treatment of cancer is the development of resistance to anti-tumor agents when used repeatedly. We described the induction of resistance, cross-resistance to cisplatin (CDDP) or vindesine (VDS) and the side effects of gemcitabine, a new Ara-C derivative, in human lung cancers, Mqnu-1 or H-73 xenografted in nude mice. We investigated the effects of 4-week treatment with gemcitabine, CDDP or VDS, followed by repeated or alternate therapy after a 4-week observation period. Gemcitabine was effective and did not show the acquired resistance when given repeatedly. In contrast, CDDP but not VDS, when given repeatedly, showed a decrease of the anti-tumor effect in the second course. Gemcitabine was still effective to the large tumor grown after CDDP or VDS therapy. Thus, gemcitabine may not develop resistance nor show cross-resistance to CDDP or VDS. In addition, repeated treatment with gemcitabine was much safer than CDDP or VDS. These results suggest that gemcitabine is a candidate for the first choice drug in cancer treatment.