Publisher Summary One of the most challenging aspects of cancer chemotherapy is the problem of resistance to clinical drugs. The reasons for clinical resistance may include pharmacokinetic or cell kinetic factors. It is generally accepted that cellular drug resistance is one of the major reasons that treatment fails. The mechanisms of resistance depend on several factors and circumstances that have given rise to the following classifications: (1) natural (de novo or intrinsic) versus acquired resistance, (2) experimental versus clinical resistance, (3) resistance developed in rodent versus in human cell lines, (4) in vitro versus in vivo resistance and ( 5 ) low versus high degree of resistance. In addition, the dose schedule may affect resistance. Basically, cellular resistance depends on the biological possibilities which are available for a mammalian cell to escape cellular injury from a cytotoxic drug. Consequently, the mechanisms of resistance found in one cellular system may also occur in another. Considering drug resistance from this point of view, all mechanisms described may be relevant. The chapter begins with a description of different mechanisms of resistance, even though they may have been documented in only one of the classes of resistance, and focuses on cellular resistance to cancer chemotherapy.