Abstract Although most metastatic cancers now have at least one effective therapy, evolution of resistance almost invariably leads to treatment failure and patient death. While often viewed as the result of a “resistance mutation,” many cancer cell resistance strategies simply involve increased expression of genes (e.g., xenobiotic metabolism) already in the human genome. Furthermore, clinical treatments to block the resistance mechanism (e.g. the MDR proteins) have generally been unsuccessful reflecting the multiplicity of available strategies. In an evolutionary context, however, the mere presence of a resistant phenotype is not sufficient for treatment failure. Rather, tumor progression requires proliferation of the resistant phenotype at a rate sufficient to produce the billions of cells necessary for clinically evident progressive disease. Importantly, the necessary molecular, cellular, and population dynamics necessary for cancer progression during treatment are deeply connected because there are often significant phenotypic costs from synthesis, maintenance, and operation of the molecular machinery of resistance that can reduce cellular proliferation and invasion particularly in the substrate-poor environment often present in clinical cancers. Evolution-based cancer treatment assumes that resistant phenotypes are invariably present prior to initiation of therapy and seeks to exploit evolutionary dynamics to delay or prevent proliferation of these cells. A specific example of this approach is adaptive therapy which is used in clinical settings in which cure is not achievable. Similar to widely accepted practices in pest management, adaptive therapy reduces or periodically withdraws treatment to maintain a stable population of treatment-sensitive cells that can use their fitness advantage (i.e. absence of the cost of resistance) to suppress proliferation of resistant phenotypes. This approach has been investigated in both pre-clinical and clinical conditions. A clinical trial in metastatic castrate-resistant prostate cancer (mCRPC) has been completed and will be discussed. Finally, when cure from a cancer treatment is possible but rare, evolutionary dynamics, based on observations in Anthropocene extinctions, can theoretically be used to increase the probability of complete eradication of the malignant population. Citation Format: Robert Gatenby. Harnessing evolutionary dynamics for control and cure of metastatic cancers [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA001.