To tackle drug resistance in targeted treatments, it is necessary to comprehend both genetic and nongenetic causes. These mechanisms include mutations in the gene targeted by the medication and the adaptive reprogramming of signalling pathways. Novel pharmaceuticals, such as combination therapy and bivalent compounds, have been created to counteract resistance mutations in different cancer-causing sites, prolonging treatment effectiveness. Nevertheless, resistance to specific protein degraders such as PROTACs and molecular glues may develop. This would need the implementation of techniques to counteract resistance caused by mutations. Furthermore, resistance to drugs that do not involve mutations, such as adaptive reprogramming and cell plasticity, poses difficulties but also provides potential for rational medication combinations and treatments that target epigenetic changes to avoid or overcome resistance. Small compounds that target transcription factors are a valuable addition to the range of tools available to combat drug resistance in cancer treatment ( ).