Analysis of the process of drug resistance indicates that it appears to be only too easy for malignancies to generate many varieties of drug-resistance mechanisms. Once a tumour has reached a certain critical size a combination of large numbers of candidate cells together with genetic instability will ensure that the collective molecular heterogeneity of the neoplasm will be immense. In retrospect, the surprising thing is not that cancers are difficult to treat with drugs but that some are highly sensitive to drug therapy and indeed are potentially curable. Although the addition of new cytotoxic agents provides a reasonably steady incremental improvement in cancer therapy outcome, these increments are small and are for the most part confined to the classes of tumour that are known already to be drug responsive. Malignancies such as pancreatic carcinoma, renal cell cancer, melanoma and nonsmall cell lung cancer are only minimally responsive to cytotoxic agents and it seems unlikely that random drug searches will yield single agents that are going to be much more effective than the drugs we currently possess. A major problem with these types of cancer seems to be the large number of different multidrug resistant mechanisms that they express. Modulation of one or two of these mechanisms is unlikely to be sufficient to render the advanced forms of the tumour curable. The greater the number of discreet mechanisms that need to be disabled then, of course, the more logistically cumbersome the treatment protocol becomes.