It is important to understand the interplay of epigenetic changes, exercise and nutrition associated with the development of obesity and type-2 diabetes because it offers insights into how environment and lifestyle factors can influence gene expression without altering the genetic code. This knowledge can lead to the development of optimal interventions and preventive strategies that could potentially decrease the rising rates of obesity and type-2 diabetes. The purpose of this review is to examine the interplay of epigenetic, exercise and nutrition on inflammation and metabolic diseases including obesity and type-2 diabetes, and to acquaint the clinicians and researchers with the current advancing and evolving field of exercise and epigenetics. The proposed mechanisms involved pertain to the development of insulin resistance in peripheral tissues and type-2 diabetes including inflammation. The benefits with regular exercise include improvement in metabolic health occurring through adaptative mechanisms in the adipose tissue, skeletal muscle, and liver as well as improvement in insulin resistance. Physical activity is defined by providing physiological characteristics of physical fitness that includes aerobic or cardiorespiratory fitness, and muscular strength and muscular endurance via regular aerobic exercise or resistance training. Exercise training encompasses training modality, exercise frequency and duration. We discuss the interplay of epigenetic mechanisms in inflammation that may contribute to the current worldwide obesity and type-2 diabetes. Specifically, epigenetic induces a change in phenotype without changes in genotype and thus the epigenome can modify the genome outcome through several processes that include DNA methylation, post-translational histone modification and gene regulation mediated by non-coding RNA (ncRNA) mechanisms that have been correlated with various metabolic and inflammatory diseases.