Drug resistance has always been a concern in cancer treatment, often blamed on the genetic complexity and instability of tumor cells. While studies of cancer cell lines have implicated an array of potential mechanisms, it has been difficult to translate these insights into clinically meaningful improvements in cancer treatment. The successful deployment of molecularly targeted therapeutics in some cancers has led to widespread optimism that this approach will become broadly applicable. Despite their early promise in the clinic, the novel therapeutics are often plagued with the age old problem of acquired drug resistance. Progress in understanding why certain patients respond and why some develop resistance can be made rapidly through studies of the drug target in tumor tissue from patient. One important lesson is that many cancers, even in the most advanced stages, continue to rely on a limited number of critical oncogenic signals for maintenance of the malignant phenotype. This article reviews the mechanisms of drug resistance to a variety of cancer therapeutics and provides an approach for how measures of drug target activity can be incorporated into clinical trial design.