Sirtuin 6 (SIRT6) is a nicotinamide adenine dinucleotide(+) (NAD(+)) dependent enzyme and stress response protein. SIRT6 has several different functions in multiple different molecular pathways related to DNA repair, glycolysis, gluconeogenesis, tumorigenesis, neurodegeneration, cardiac hypertrophic responses, and more. SIRT6 is a main regulator of metabolism and lifespan and its importance has been implicated in the prevention against aging-related diseases. SIRT6 depletion enhanced chemosensitivity of human hepatoma cells by downregulating MDR1 expression through suppressing C/EBPbeta. SIRT6 may serve as a novel target to enhance chemosensitivity in HCC cells.