Drug resistance has complicated chemotherapy of neoplastic disease since the early beginnings of the field. Successful use of drug therapy requires that tumor cells be more drug-responsive than the tissue of origin. This can occur with rapidly-dividing tumors which will be highly-responsive to drugs toxic in the S-phase of the cell cycle. Another drug sensitive population will consist of neoplastic cells unable to repair drug-induced damage which can be repaired by normal host cells. Even if one of these conditions is initially found, mutational events leading to drug resistance often occur. The most thoroughly explored mode of drug resistance involves MDR (multidrug resistance), an outward transport system which limits penetration of a variety of cytotoxic agents into the cytoplasm and nucleus. MDR is expressed by many normal cell types, and attempts at MDR circumvention appear to lead to new modes of host toxicity. It appears that new directions in cancer therapy will be needed to yield responses in the common slow-growing tumors which tend to be inherently drug-resistant.