Multiple factors cause atherosclerosis, and its pathogenesis is complex and has not been fully elucidated.Polyunsaturated fatty acids, a member of the fatty acid family, are critical nutrients for mammalian growth and development. Types and intakes of polyunsaturated fatty acids, and fatty acid desaturase can affect the course of atherosclerotic disease. Fatty acid desaturase gene cluster can regulate fatty acid desaturase activity and further affect atherosclerosis. Based on the metabolic and genetic perspectives, this article reviewed the research progress of the effects of polyunsaturated fatty acids on atherosclerosis regulated by fatty acid desaturase and the relationship between genetic variants of the fatty acid desaturase gene cluster and atherosclerotic cardiovascular disease was summarized.