Drug resistance is the most common cause of relapses and represents a major limitation for successful management of advanced cancers. Patients with relapse often experience an aggressive progression of the disease. The use of conventional chemotherapy drug combinations remains of limited success given the common occurrence of a broad cross-resistance toward structurally and functionally unrelated drugs. Initial optimism surrounding modulation of single cellular drug resistance markers identified in preclinical models has resulted in very limited predictive and clinical benefit primarily because of alternative mechanisms that operate in drug resistant cancer cells. Even modulators can become entangled in the same problems that they were intended to solve, namely cell resistance to the modulator itself. The recent shift in the use of targeted agents, particularly those targeting tyrosine kinase receptors and signaling components, has provided exciting clinical results. In particular, recent clinical trials have demonstrated the utility of these targets as surrogate markers to guide the selection of patient populations susceptible to respond to treatment. Yet, these optimisms are tempered in part because resistance to targeted therapies is now documented to occur in experimental models and in the clinic. This review interface mechanisms of drug resistance to targeted therapies versus non-specific chemotherapy, with emphasis on fundamental challenges to be resolved to improve the therapeutic management of refractory cancers.