Dietary modification is the first-line approach to weight loss for patients with obesity to improve cardiometabolic health. Weight-loss diets modifying macronutrient compositions have shown varying degrees of short-term success; however, long-term effects often include subsequent weight regain, and the mechanisms underlying individual variability in long-term successful weight loss remain incompletely understood. Research such as the POUNDS Lost trial highlights that tailoring diets to personal preferences and biological characteristics may improve long-term weight-loss success, highlighting the need for personalized approaches in nutrition and recent advances in precision nutrition through insights from genetics, epigenetics, metabolomics, and related fields. This chapter reviews the primary and ancillary findings from the Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) trial, focusing on diet composition, weight loss, metabolic outcomes, and advancement in precision nutrition.