The chapter discusses the multifaceted problem of drug resistance in cancer and proposes a framework to address it. It highlights key determinants of drug resistance, including tumor burden, growth kinetics, tumor heterogeneity, physical barriers, the immune system, and microenvironment, as well as undruggable cancer drivers and the consequences of therapeutic pressures. The authors propose four general solutions: early detection of tumors, adaptive monitoring during therapy, adding novel drugs and improving pharmacological principles, and identifying cancer cell dependencies through high-throughput synthetic lethality screens and computational modeling. These approaches aim to enhance the probability of cure by preventing, delaying, or reversing resistance to therapy. The chapter also explores the challenges and potential strategies for each of these areas, emphasizing the need for integrated and adaptive therapeutic interventions.The chapter discusses the multifaceted problem of drug resistance in cancer and proposes a framework to address it. It highlights key determinants of drug resistance, including tumor burden, growth kinetics, tumor heterogeneity, physical barriers, the immune system, and microenvironment, as well as undruggable cancer drivers and the consequences of therapeutic pressures. The authors propose four general solutions: early detection of tumors, adaptive monitoring during therapy, adding novel drugs and improving pharmacological principles, and identifying cancer cell dependencies through high-throughput synthetic lethality screens and computational modeling. These approaches aim to enhance the probability of cure by preventing, delaying, or reversing resistance to therapy. The chapter also explores the challenges and potential strategies for each of these areas, emphasizing the need for integrated and adaptive therapeutic interventions.