The metabolic syndrome (MetS) is a very common disease associated with an increased risk of type 2 diabetes mellitus and cardiovascular disease. The diverse clinical characteristics of the MetS 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 disease. Research indicates a major role for genetic susceptibility to the MetS. However, the human genome has not changed markedly in the last decade but the prevalence of the condition has increased exponentially, illustrating the importance of gene-environmental interactions. Dietary fat is an important environmental factor which can modify the development of the MetS. Genetic background can interact with habitual dietary fat composition, affecting predisposition to the MetS. Recent research indicates that currently ineffective therapeutic dietary recommendations may require a 'personalised nutrition' approach, wherein the genetic profile may determine the responsiveness of patients to specific dietary fatty acid interventions. 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 MetS. This review will explore the interactions between genetic background and dietary exposure/nutritional therapy.