Diet-gene interaction has been identified to play a crucial role in health maintenance, which could curtail processes that could lead to disease development or progression. Moreover, the availability of nutrients in the diet has a direct or an indirect gene influence with a high impact on metabolism that could predispose to health disorders at the epigenetic level when altered. Interestingly, it has been observed that epigenetics could frequently provide adequate insight into several factors responsible for the proper regulation of gene expression, which might be independent of the genetic sequence in a biological system. However, understanding the relationship that exists between epigenetic interactions and diet toward the modification of gene structure and gene expression is paramount. Therefore, this chapter focuses on epigenetics and its role in gene regulation via DNA methylation, modification of histone, and microRNA modification; nutrient-gene interaction and its efficacy in diseases like obesity, diabetes, aging, and cancer were also discussed.