Drug resistance is a major factor that frustrates treatment of the disease in patients with bacterial infections. This issue is multifactorial in nature because it involves a complex interaction between genetic and epigenetic modifications, drug-metabolizing, enhanced DNA repair, efflux pump systems, and interactions in the tumor microenvironment. Recent developments in molecular biology, such as next-generation sequencing and CRISPR-Cas9, have shed some light into these complex resistance mechanisms leading to the discovery of new therapeutic targets. New approaches, which includes combination therapy, immunotherapy, and nanomedicine, provide an effective way to fight resistance. Nevertheless, biomarkers, personalized medicine and tumor microenvironment have to be further explored, as they will help to make cancer care more effective in overcoming this chronic problem. This review endeavrees to summarize the latest knowledge on drug resistance mechanisms in cancer, the emergence of therapeutic options to overcome this resistance and share future research advances in this most fundamental field.