Obesity has been characterized as a state of chronic inflammation. Inflammatory signaling not only causes peripheral insulin resistance, but also promotes neuronal insulin and leptin resistance, which further propagates a positive energy balance. Upon development of obesity, numerous conditions, including increased circulating cytokine concentrations and cell autonomous dysregulation of homeostatic signaling pathways, such as the endoplasmic reticulum stress response, promote activation of stress kinases, to cause peripheral insulin as well as central insulin and leptin resistance. Recently, activation of toll-like receptor (TLR) signaling has been recognized as an alternative activator of obesity-induced inflammation. In this paper, we review recent progress in defining the molecular basis of obesity-associated TLR activation and its role in the development of metabolic syndrome.