The metabolic syndrome is a very common disease associated with an increased risk of type 2 diabetes mellitus (T2DM) and CVD. The clinical characteristics of the metabolic syndrome include insulin resistance, dyslipidaemia, abdominal obesity and hypertension. The diverse clinical characteristics illustrate the complexity of the disease process, which involves several dysregulated metabolic pathways. Thus, multiple genetic targets must be involved in the pathogenesis and progression of the metabolic syndrome. Nevertheless, the human genome has not changed markedly in the last decade but the prevalence of the metabolic syndrome has increased exponentially, which illustrates the importance of gene–environmental interactions. There is good evidence that nutrition plays an important role in the development and progression of the metabolic syndrome. Indeed, obesity is a key aetiological factor in the development of the metabolic syndrome. Understanding the biological impact of gene–nutrient interactions will provide a key insight into the pathogenesis and progression of diet-related polygenic disorders, including the metabolic syndrome. The present paper will explore the interactions between genetic background and dietary exposure or nutritional therapy, focusing on the role of dietary fatty acids within the context of nutrient regulation of gene expression and individual responsiveness to dietary therapy. Only with a full understanding of gene–gene, gene–nutrient and gene–nutrient–environment interactions can the molecular basis of the metabolic syndrome be solved to minimise the adverse health effects of obesity and reduce the risk of the metabolic syndrome, and subsequent T2DM and CVD.