The Metabolic Syndrome, which includes obesity and type 2 diabetes, is reaching alarming proportions. A key factor is insulin resistance, defined as a reduced ability of insulin to stimulate glucose utilization and storage. Compelling evidence links insulin resistance with an excess fatty acid supply over energy need, resulting in lipid accumulation in non-adipose tissues. The AMPK pathway plays a key role in sensing and regulating tissue energy metabolism, influencing fuel metabolism in tissues including muscle and liver. A number of its actions could improve muscle insulin sensitivity at least partly by increasing fatty acid oxidation and diminishing synthesis of malonyl CoA, glycerolipids, ceramide and other molecules linked to insulin resistance, although the extent of these effects, particularly in the human context, is uncertain. Secondly, its activation could bypass the metabolic block associated with insulin resistance. Thirdly, it is possible that a dysregulation of the AMPK pathway may itself contribute to the metabolic derangement associated with insulin resistance. These issues are important in considering the AMPK pathway as a therapeutic target in insulin resistant states.