Clinical resistance is usually assumed to be due to the initial presence or selection of drug-resistant cells in tumors. While important, it is suggested in this review that genetically-determined causes of cellular resistance represent but one cause (and possibly not the major cause) of effective clinical resistance of solid tumors. Factors that depend on tumor physiology, and on the microenvironment and three-dimensional structure of solid tumors, may have a profound influence on their sensitivity to anti-cancer drugs. Particular emphasis is placed on the limited penetration of some drugs from tumor blood vessels and on the repopulation of tumor cells between courses of chemotherapy as causes of clinical resistance. Both of these mechanisms are amenable to modulation to improve therapeutic index. Failure to recognize that clinical drug resistance cannot be explained entirely by mechanisms operative at the level of the single cell may lead to disappointing results in clinical trials such as, for example, clinical failure of the strategy of reversal of multidrug resistance.