Resistance of malignant cells to chemotherapy and molecularly targeted therapy is a major roadblock in our effort to cure cancer. A variety of underlying mechanisms have been described, some of which are shared between resistance to chemotherapy and resistance to molecularly targeted therapy. Although the influence of genetic mutations in the development of drug resistance is beyond question, many examples now support the contribution of epigenetic changes to drug resistance. Several clinical trials are under way to explore the effectiveness of epigenetics-targeting drugs to reverse or overcome resistance to cancer therapies. In addition to these strategies, we suggest a complementary approach that could utilize epigenetics-targeting drugs to prevent drug resistance.