In contrast to conventional chemotherapeutic agents, modern anticancer therapies are aimed at attacking specific targets in a tumor. While these therapies show promising clinical effects, their success is limited by the development of resistance to the antitumor agent, a phenomenon that is well known in regular cancer therapies. As illustrated in a novel study by Debies and colleagues in The Journal of Clinical Investigation, mouse models for cancer serve as promising tools for advancing our understanding of the tumor response to targeted therapy. However, the experimental setup and selected model system may evoke unexpected escape mechanisms. Here, we discuss the promises and pitfalls of these approaches.