Here, roles of Sirt6 in atherosclerosis, coronary heart diseases, cardiac I/R injury, hypertension, cardiac hypertrophy, cardiac fibrosis, heart failure, diabetic cardiomyopathy, glucose metabolisms, and DM are reviewed, with emphasis on the molecular network through which Sirt6 regulates myriad CVDs. The gene discussed is SIRT6; the disease is atherosclerosis.