Obesity is a major health problem in industrialized societies often associated with diabetes, insulin resistance, and hepatic steatosis. This review addresses the hypothesis that elongation of long-chain fatty acids family member 6 (Elovl6) has an important role in energy metabolism and insulin sensitivity. Elovl6 is a microsomal enzyme involved in the elongation of saturated and monounsaturated fatty acids with 12, 14, and 16 carbons. Mice with targeted disruption in the gene for Elovl6 (Elovl6 (-/-)) are resistant to diet-induced insulin resistance despite their hepatosteatosis and obesity being similar to that of the wild-type mice. Protection against diet-induced insulin resistance in Elovl6 (-/-) mice is partially due to restoration of hepatic insulin receptor substrate-2 and suppression of hepatic protein kinase C epsilon, resulting in restoration of Akt phosphorylation. We suggest that inhibition of this elongase could be a new therapeutic approach for the treatment of insulin resistance, diabetes, cardiovascular disease, and other metabolic diseases.