Diabetes mellitus (DM) is considered a global pandemic and its incidence continues to grow worldwide. The most common treatments for controlling diabetes focus on glucose control as a means to reduce long-term complications. Major changes in diet have taken place over the past 10,000 years since the beginning of the Agricultural Revolution: however, human genes have not changed. We now live in a nutritional environment that differs from that for which our genetic constitution was selected. Nutrients and dietary patterns are central issues in the prevention, development and treatment of DM. Nutritional genomics studies generally focus on dietary patterns according to genetic variations, the role of gene-nutrient interactions, gene-diet-phenotype interactions and epigenetic modifications caused by nutrients; these studies facilitate an understanding of the early molecular events that occur in DM and contribute to the identification of better biomarkers and diagnostic tools for the disease. In particular, this approach will help develop tailored diets that maximize the use of nutrients and other functional ingredients present in food, which will aid in the prevention and delay of DM and its complications. Here, we provide an understanding of the role of gene variants and nutrient interactions, and discuss the importance of nutrients and dietary patterns on gene expression.