Plant-based diets are clearly identified as the most protective for our health; it is now important to focus on the good food associations and the beneficial constituents in plant foods. Based on a growing body of evidence, some categories of plant food bioactives (PFB) are increasingly considered to play a key role in the cardiometabolic health effects associated with plant foods consumption. However, the heterogeneity in responsiveness to PFB intake that is frequently observed in clinical trials can hinder the identification of the effects of these compounds in specific subpopulations and likely lead to underestimating their actual contribution to the health effects of plant foods. A range of factors, including genetic background, gut microbiota composition, age, sex, health status, could explain these interindividual variations and they may differ depending on the compounds. Despite some known examples related to few compounds that clearly testify that interindividual variability (IVV) in response to PFB consumption exists, only limited and scattered data are available on the subject. To tackle the complexity of this question through a multidimensional approach, the European COST POSITIVe network (https://www6.inra.fr/cost-positive) has gathered a large community of experts in nutrition and plant food bioactives, food science, clinical research, microbiology, gut microbiome, genetics, nutrigenomics, bioinformatics, cellular and molecular biology. These experts have analysed in a systematic way the currently-fragmented knowledge in the field with the aim to: (1) evaluate the extent of the IIV for the major categories of PFB and identify the main factors responsible for between-subject variation in both the ADME and the biological responsiveness regarding cardiometabolic endpoints; (2) integrate the main findings of the network to identify the gaps in knowledge and needs for future research, and also (3) examine how this knowledge could be translated into concrete applications for the different categories of stakeholders, including food industry, policy makers and consumers. A good knowledge of the determinants of the IIV in response to the consumption of PFB is a prerequisite to enable the development and production of plant food products satisfying the nutritional needs and conferring benefits to different categories of populations. The development of a science-based precision nutrition approach focusing on plant foods rich in specific bioactive compounds could constitute a promising strategy for tackling the dramatic burden of metabolic and cardiovascular diseases.