The resistance of cancer cells to anti-neoplastic agents is a major attribute of malignancy. Kinetic drug resistance develops as the tumor burden increases, and is reversible when the cell mass can be reduced. Genetic drug resistance, in contrast, results in the acquisition of possibly irreversible resistance by random cell mutation. The latter mechanism, and one of its corollaries, that rapidly alternating drug regimens could prevent the advent of new resistant cell lines, have been the subject of many studies in the last decade. The endpoint to evaluate in such studies should be an increase in failure-free survival, since such prevention cannot have any influence in the complete remission rates. A review of the clinical trials in Hodgkin's disease suggests that failure-free survival rates are in fact improved with the alternating schedules. On the other hand, dose-intensification is presently under study as a means of overcoming kinetic drug resistance, thereby increasing the complete remission rates, and has recently proved effective in the prolongation of survival in different malignancies. Further understanding of the mechanisms of drug resistance and the prospective appraisal of the combination of both high-dose therapy and alternating drug treatments should result in a better outcome, mostly for patients with large tumor burdens or other high risk factors.

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