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The pistachio is regarded as a relevant source of biologically active components that, compared to other nuts, possess a healthier nutritional profile with low-fat content composed mainly of monounsaturated fatty acids, a high source of vegetable protein and dietary fibre, remarkable content of minerals, especially potassium, and an excellent source of vitamins, such as vitamins C and E. A rich composition in terms of phytochemicals, such as tocopherols, carotenoids, and, importantly, phenolic compounds, makes pistachio a powerful food to explore its involvement in the prevention of prevalent pathologies. Although pistachio has been less explored than other nuts (walnut, almonds, hazelnut, etc.), many studies provide evidence of its beneficial effects on CVD risk factors beyond the lipid-lowering effect. The present review gathers recent data regarding the most beneficial effects of pistachio on lipid and glucose homeostasis, endothelial function, oxidative stress, and inflammation that essentially convey a protective/preventive effect on the onset of pathological conditions, such as obesity, type 2 diabetes, CVD, and cancer. Likewise, the influence of pistachio consumption on gut microbiota is reviewed with promising results. However, population nut consumption does not meet current intake recommendations due to the extended belief that they are fattening products, their high cost, or teething problems, among the most critical barriers, which would be solved with more research and information.