For many years the mechanisms of intrinsic or acquired drug resistance have been the major object for molecular oncologists and clinicians, because resistance to chemotherapy critically limits the outcome of cancer treatment. Initially, the interaction of a drug with its molecular target that yields a lethal lesion has been studied - at the target level or upstream of this interaction (drug influx and efflux, detoxification, DNA repair etc.). Later, it was discovered that downstream cellular responses to a given DNA lesion can determine the outcome of the therapy, focusing the investigation on the processes of the programmed cell death. More recently a new phenomenon of drug resistance has been discovered, called Cell Adhesion-Mediated Drug Resistance. It is based on the adherence of cells to extracellular matrix proteins through adhesive molecules such as integrins. Integrins are cell surface heterodimeric receptors that mediate cell-extracellular matrix adhesion. They trigger many intracellular signaling pathways involved in a cell proliferation, survival/apoptosis, shape, polarity, motility, and differentiation. Integrins may protect cancer cells from an array of cytotoxic agents in several ways. This review will focus on the role of integrins in conferring resistance to tumor cells. We will discuss specific signal transduction pathways initiated by integrin ligation as a source of potential therapeutic targets for the fight against cancer.