Targeted therapies have revolutionized cancer treatment. Unfortunately, their success is limited due to the development of drug resistance within the tumor, which is an evolutionary process. Understanding how drug resistance evolves is a prerequisite to a better success of targeted therapies. Resistance is usually explained as a response to evolutionary pressure imposed by treatment. Thus, evolutionary understanding can and should be used in the design and treatment of cancer. In this article, drug-resistance to targeted therapies is reviewed from an evolutionary standpoint. The concept of apoptosis-induced compensatory proliferation (AICP) is developed. It is shown that AICP helps to explain some of the phenomena that are observed experimentally in cancers. Finally, potential drug targets are suggested in light of AICP.