There is growing support for the hypothesis that obesity is an inflammatory condition leading to chronic activation of the innate immune system, which ultimately causes progressive impairment of glucose tolerance. Experimental studies in animals and evidence from prospective and longitudinal studies in humans are consistent with an etiologic role of subclinical inflammation in the pathogenesis of type 2 diabetes, primarily as a mediator of obesity-induced insulin resistance. However, the exact chain of molecular events linking overnutrition, activation of the innate immune system, and impairment of insulin signaling in peripheral tissues remains incompletely understood. Notwithstanding this limitation, treating the underlying subclinical inflammation may constitute a novel approach to prevention and/or treatment of type 2 diabetes.