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This review documents our rapidly changing perspectives on the function of fatty acid synthase-catalyzed endogenous fatty acid biogenesis in cancer biology.Up-regulation of fatty acid synthase gene expression and fatty acid synthase biosynthetic activity are molecular events accompanying the pathogenesis and natural history of cancer disease. First, the increased fatty acid synthase gene expression in precursor, preinvasive and invasive cancer lesions appears to represent an indirect, early epiphenomenon, occurring in response to a microenvironment containing regions of poor oxygenation and high acidity due to, for example, lack of an adequate angiogenesis and/or nutritional supply. Second, aberrant transduction cascades driven by cancer-associated oncogenic changes subvert the downregulatory effects of circulating fatty acids. Third, fatty acid synthase-dependent endogenous fatty acid metabolism actively contributes to cancer evolution by specifically regulating the expression, activity and/or cellular localization of proteins closely related to malignant transformation and/or cancer progression.Fatty acid synthase-catalyzed endogenous fatty acid metabolism appears to be an obligatory acquisition selecting a biologically aggressive sub-group of cancer cells capable of growth and survival upon stresses such as hypoxia, low pH and/or nutritional deprivation. Considering that an ever-growing body of evidence demonstrates that fatty acid synthase-driven signalling actively regulates key cancer-controlling networks, we may hereafter redefine fatty acid synthase as a metabolic oncogene in human cancer cells.