Obesity is associated with significantly increased cardiovascular (CV) risk and mortality. Several molecular mechanisms underlying this association have been implied, among which the intestinal barrier has gained a growing interest. In experimental models of obesity, significant alterations in the intestinal barrier lead to increased intestinal permeability, favoring translocation of microbiome-derived lipopolysaccharide to the bloodstream. This has been shown to result in a two- to threefold increase in its serum concentrations, a threshold named ‘metabolic endotoxemia’ (ME). ME may trigger toll-like receptor 4-mediated inflammatory activation, eliciting a chronic low-grade proinflammatory and pro-oxidative stress status, which may result in high CV risk and target-organ damage. In this review, we discuss the potential molecular implications of ME on several CV risk factors, such as obesity, insulin resistance, dyslipidemia, and oxidative stress, as well as its potential impact on the development of CV target-organ disease.