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Metabolic and genotoxic stresses that arise during tumor progression and anti-cancer treatment, respectively, can impose a selective pressure to promote cancer evolution in the tumor microenvironment. This process ultimately selects for the most "fit" clones, which generally have a cancer stem cell like phenotype with features of drug resistance, epithelial-mesenchymal transition, invasiveness, and high metastatic potential. From a bioenergetics perspective, these cancer stem-like cells (CSCs) exhibit mitochondria-centric energy metabolism and are capable of opportunistically utilizing available nutrients such as fatty acids to generate ATP and other metabolic substances, providing a selective advantage for their survival in an impermissible environment and metabolic context. Thus, diverse therapeutic strategies are needed to efficiently tackle these CSCs and eliminate their advantage. Here, we review the metabolic and bioenergetic characteristics and vulnerabilities specific to CSCs, which can provide an unprecedented opportunity to curb CSC-driven cancer mortality rates. We particularly focus on the potential of a CSC bioenergetics-targeted strategy as a versatile therapeutic component of treatment modalities applicable to most cancer types. A cancer bioenergetics-targeted strategy can expand the inventory of combinatorial regimens in the current anti-cancer armamentarium. [ABSTRACT FROM AUTHOR] more...