As obesity has become a major global public health challenge, a large number of studies have analyzed different strategies aimed at inducing a negative energy balance and, consequently, body weight loss. However, most existing weight loss programs are generally unsuccessful, so several interventions have been carried out to identify physiologic and behavioral factors concerning this variability in order to implement more personalized treatment. Nowadays, an individualized approach is being proposed through so-called personalized nutrition, whereby not only the phenotype but also the genotype is used for customized nutrition treatment. Regarding body weight regulation, similar to 70 polymorphisms have been identified in or near genes related to energy expenditure, appetite, adipogenesis, insulin resistance, and lipid metabolism. Although personalized nutrition refers mainly to genetic makeup, recent advances in the investigation of the epigenome and themicrobiome open the door to implement more personalized recommendations for body weight management. In this context, recent studies have demonstrated the existence of several epigenetic markers that may modify gene expression and could be involved in the outcome of weight loss interventions. Moreover, different studies have shown that dietary interventions could affect the composition of gut microbiota and have an impact on body weight. The integration of nutrigenetic, epigenetic, and metagenomic data may lead to the design of more personalized dietary treatments to prevent chronic diseases and to optimize the individual's response to dietary interventions.