Drug resistance has profoundly limited the success of cancer treatment, driving relapse, metastasis, and mortality. Nearly all anticancer drugs and even novel immunotherapies, which recalibrate the immune system for tumor recognition and destruction, have succumbed to resistance development. Engineers have emerged across mechanical, physical, chemical, mathematical, and biological disciplines to address the challenge of drug resistance using a combination of interdisciplinary tools and skill sets. This review explores the developing, complex, and under-recognized role of engineering in medicine to address the multitude of challenges in cancer drug resistance. Looking through the "lens" of intrinsic, extrinsic, and drug-induced resistance (also referred to as "tolerance"), we will discuss three specific areas where active innovation is driving novel treatment paradigms: (1) nanotechnology, which has revolutionized drug delivery in desmoplastic tissues, harnessing physiochemical characteristics to destroy tumors through photothermal therapy and rationally designed nanostructures to circumvent cancer immunotherapy failures, (2) bioengineered tumor models, which have benefitted from microfluidics and mechanical engineering, creating a paradigm shift in physiologically relevant environments to predict clinical refractoriness and enabling platforms for screening drug combinations to thwart resistance at the individual patient level, and (3) computational and mathematical modeling, which blends in silico simulations with molecular and evolutionary principles to map mutational patterns and model interactions between cells that promote resistance. On the basis that engineering in medicine has resulted in discoveries in resistance biology and successfully translated to clinical strategies that improve outcomes, we suggest the proliferation of multidisciplinary science that embraces engineering.