Purpose of this Review This review assesses the latest evidence linking short-chain fatty acids (SCFA) with host metabolic health and cardiovascular disease (CVD) risk and presents the latest evidence on possible biological mechanisms. Recent Findings SCFA have a range of effects locally in the gut and at both splanchnic and peripheral tissues which together appear to induce improved metabolic regulation and have direct and indirect effects on markers of CVD risk. Summary SCFA produced primarily from the microbial fermentation of dietary fibre appear to be key mediators of the beneficial effects elicited by the gut microbiome. Not only does dietary fibre fermentation regulate microbial activity in the gut, SCFA also directly modulate host health through a range of tissue-specific mechanisms related to gut barrier function, glucose homeostasis, immunomodulation, appetite regulation and obesity. With the increasing burden of obesity worldwide, the role for gut microbiota-generated SCFA in protecting against the effects of energy dense diets offers an intriguing new avenue for regulating metabolic health and CVD risk.