Insulin resistance and cardiovascular disease share common pathophysiological mechanisms, as the chronic activation of the innate immune system. This system constitutes the first line of body's defense and is constituted by different barriers (e.g., epithelia, adipose tissue) and different blood and tissue components (e.g., macrophages, neutrophils). This system generates the acute-phase response in which different acute-phase proteins and cytokines are produced in response to different aggressions as infections and traumatisms. The aim of this response is to eradicate these agents, to repair the harmed tissues, and, through increased insulin resistance, to optimize the energetic substrates, which will be drained to vital tissues and organs (i.e., brain and the immune system). Evolutionary pressures have led to survival of the fittest individuals, those with the genetics that allows the best defense against infection and periods of famine. Evidence is reported according to which gene polymorphisms in the molecules regulating the inflammatory cascade are associated with body composition, insulin action, and characteristics of the metabolic syndrome. The evolutive advantages of increased inflammatory responses, hypersecretion of proinflammatory cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, and IL-18], or decreased anti-inflammatory molecules (adiponectin, certain TNF-alpha isoforms, soluble CD14, etc.), would lead in westernized countries to chronic inflammation conditions, such as obesity and type 2 diabetes, resulting in cardiovascular disease.