Abstract In early breast carcinogenesis, neoplastic cells grow in multiple layers towards the lumens of ducts, which subjects the periluminal cells to harsh conditions of low oxygen, low pH, and nutrient deprivation. Adaptation to these harsh conditions is a pre-requisite for survival of incipient tumor cells and also responsible for selecting cells with a more aggressive phenotype. Based on the first principle of Darwinian evolution, common phenotypes of cancer cells must have conferred a selective advantage at some point during their evolutionary trajectory. Adaptations are initially acute and reversible, but eventually Darwinian selection results in cells with hardwired phenotypes. A prominent example of this is aerobic glycolysis, or the Warburg Effect (WE), wherein cells are hard-wired to ferment glucose, even in the presence of oxygen. WE provides and evolutionary advantage which leads to higher fitness of the cancer cells, who have acquired mechanisms of adaptation, such as autophagy and lysosome redistribution. Notably, a WE is highly correlated with a cancer’s metastatic potential and poor outcome. Hence, a major question in carcinogenesis is: “What are the mechanisms by which a harsh microenvironment eventually selects for hard-wired (heritable) phenotypes, such as a WE?”. Rather than simply selection of pre-existing phenotypes, we contend that the microenvironment actively induces phenotypic diversity through a systematic set of epigenetic and genetic alterations. Citation Format: Mehdi Damaghi. Selection for a glycolytic phenotype [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 IA023.