Classically, studies of drug resistance in cancer have focused on the molecular biology of single cancer cells. These types of studies have provided important information regarding certain drug resistance mechanisms, including mechanisms that reduce intracellular drug accumulation, alter or repair drug-induced damage, and reduce drug-induced apoptosis. While these cellular mechanisms undoubtedly contribute to the overall phenomenon of drug resistance, it is now evident that the tumor cell microenvironment also influences how a tumor cell behaves and responds to cytotoxic drugs or radiation. Two different forms of tumor cell-environmental interaction may explain how some tumor cells survive initial drug exposure and eventually express classical mechanisms of drug resistance. The first form involves soluble mediators, such as interleukins, that are secreted by non-tumor, stromal cells. Interleukin-6 (IL-6) is a classical example of how a soluble mediator secreted by the tumor microenvironment is capable of enhancing tumor cell survival and perhaps blocking apoptosis. The second form of tumor cell-environment interaction requires direct cell contact and has been given the term cell-adhesion-mediated drug resistance (CAM-DR). In this case, binding extracellular matrix ligands in the tumor microenvironment may activate cell adhesion molecules, such as the integrins, and these interactions result in the activation of signal transduction pathways that block drug-induced apoptosis. Interrupting the tumor cell-environment interactions or the associated signal transduction pathways may represent a new approach for the treatment of cancer. Copyright 1999 Harcourt Publishers Ltd.