Inflammation has been recognized as a core component of obesity-induced metabolic disease. However, a major question in biology is how is inflammation sensed in circumstances of obesity and nutrient overload? It has become widely accepted that the activation of toll-like receptor 4 (TLR4) in immune cells such as macrophages, links obesity to the development of chronic tissue inflammation and metabolic disease. Specifically, it is thought that long chain saturated free fatty acids, such as palmitate, are agonistic ligands for TLR4 in macrophages, initiating inflammation and consequently promoting the development of obesity related pathologies. Using several different experimental approaches we provide evidence that long chain saturated free fatty acids, such as palmitate are, in fact, not ligands for TLR4. However, and consistent with previous reports (Shi et al. J Clin Invest, 2006; Nguyen et al. J Biol Chem, 2007), we have demonstrated that bone marrow-derived macrophages from TLR4 knockout mice and C3H/HeJ mice (which have a naturally occurring mutation of TLR4) mice display a completely suppressed inflammatory response, as measured by phosphorylation of JNK, to palmitate treatment. I will discuss the results of experiments that we have conducted that attempt to reconcile these apparently paradoxical observations.