Evolutionary game theory mathematically conceptualizes and analyzes biological interactions where one’s fitness not only depends on one’s own traits, but also on the traits of others. Typically, the individuals are not overtly rational and do not select, but rather, inherit their traits. Cancer can be framed as such an evolutionary game, as it is composed of cells of heterogeneous types undergoing frequency-dependent selection. In this article, we first summarize existing works where evolutionary game theory has been employed in modeling cancer and improving its treatment. Some of these game-theoretic models suggest how one could anticipate and steer cancer’s eco-evolutionary dynamics into states more desirable for the patient via evolutionary therapies. Such therapies offer great promise for increasing patient survival and decreasing drug toxicity, as demonstrated by some recent studies and clinical trials. We discuss clinical relevance of the existing game-theoretic models of cancer and its treatment, and opportunities for future applications. We discuss the developments in cancer biology that are needed to better utilize the full potential of game-theoretic models. Ultimately, we demonstrate that viewing tumors with an evolutionary game theory approach has medically useful implications that can inform and create a lockstep between empirical findings, and mathematical modeling. We suggest that cancer progression is an evolutionary game and needs to be viewed as such.Competing Interest StatementThe authors have declared no competing interest.Funding StatementThis research was supported by two European Union's Horizon 2020 research and innovation programs under the Marie Sklodowska-Curie grant agreement No's 690817 and 955708, the Dutch National Foundation (NWO) Grant number OCENW.KLEIN.277, the James S. McDonnell Foundation grant, Cancer therapy: Perturbing a complex adaptive system, a V Foundation grant, NIH/National Cancer Institute (NCI) R01CA170595, Application of Evolutionary Principles to Maintain Cancer Control (PQ21), NIH/NCI U54CA143970-05 Physical Science Oncology Network (PSON) Cancer as a complex adaptive system and Austrian Science Fund (FWF): DK W1225-B20. The last author wants to thank to her daughter Julia for keeping her awake during nights, which allowed her to work on this paper.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:For this paper we have not conducted any clinical trials.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThere was no original data created for this manuscript.