Unresolved ER stress is involved in the onset and progression of several obesity-related metabolic disorders, including dyslipidemia and insulin resistance. Different epigenetic modifications may regulate ER stress response and consequently disease risks. These epigenetic phenomena encompass DNA and histone methylation patterns in ER stress genes and downstream signaling molecules, as well as microRNA expression. Our results suggest potential associations of methylation signatures at ER regulatory genes in white blood cells with an abdominal/central obesity marker (waist circumference), dyslipidemia, and insulin resistance. Interestingly, most of these genes were implicated in ER stress, as revealed by pathway enrichment analysis. Together, these findings add knowledge into the current understanding of relationships between obesity and accompanying complications with epigenetics and ER stress. Here, we comment about the implication of ER stress in central/abdominal adiposity, dyslipidemia, and insulin resistance, with an emphasis on the role that epigenetics may play on these pathological processes.