Diet is an important, modifiable lifestyle factor of cardiometabolic disease risk, and an improved diet can delay or even prevent the onset of disease. Recent evidence suggests that individuals could benefit from diets adapted to their genotype and phenotype: that is, personalized nutrition. A novel strategy is to tailor diets for groups of individuals according to their metabolic phenotypes (metabotypes). Randomized controlled trials evaluating metabotype-specific responses and nonresponses are urgently needed to bridge the current gap of knowledge with regard to the efficacy of personalized strategies in nutrition. In this Perspective, we discuss the concept of metabotyping, review the current literature on metabotyping in the context of cardiometabolic disease prevention, and suggest potential strategies for metabotype-based nutritional advice for future work. We also discuss potential determinants of metabotypes, including gut microbiota, and highlight the use of metabolomics to define effective markers for cardiometabolic disease-related metabotypes. Moreover, we hypothesize that people at high risk for cardiometabolic diseases have distinct metabotypes and that individuals grouped into specific metabotypes may respond differently to the same diet, which is being tested in a project of the Joint Programming Initiative: A Healthy Diet for a Healthy Life.