New insights into cancer biology have allowed the definition of pathways critical to the success of the cancer cell. These include enhanced activity of positive regulators of cell proliferation, including oncogenes, and loss of tumor suppressor gene function; inactivation of cell death or enhancement of srvival functions; activation of telomerase, and enhanced ability of tumor cells to invade and reorganize host stroma. It follows then that these pathways may also mediate drug resistance, in a way that is fundamentally different from classically defined mechanisms for drug resistance which focus on altered handling of the drug or the drug's target by the resistant tumor cell. It is expected that resistance will occur that is predicated on altered pathway predominance in a tumor and altered tumor microenvironment. Cases which exemplify this possibility are presented, including up-regulation of angiogenesis-related regulators in relation to inhibition of EGF-related proliferative and angiogenesis-promoting functions. The implications of this thinking in relation to development of combination regimens targeting distinct pathways are considered.