Sirtuin 6 (SIRT6) is a nicotinamide adenine dinucleotide (NAD)-dependent enzyme. It is a novel member of the sirtuin family that has been shown to have an important role in various molecular pathways in glycolysis, cancer, and neurodegenerative responses. Recently, SIRT6 has emerged as a prominent research issue because its biochemical activity and regulation are possibly associated with human metabolism and disease. In this review, we summarized the connection between SIRT6 and glycolytic metabolism; discussed recent developments in the involvement of SIRT6 in a variety of life-threatening illnesses, including cancer, neurodegenerative diseases and cardiovascular disease; and explored possible treatment approaches for those diseases with SIRT6. This review provides insights into the role of SIRT6 in disease.