Emerging technologies in nutrigenomics and deep phenotyping have allowed us to collect a vast range of data on genetic indicators, clinical biomarkers, sensitive body composition metrics and dietary intake data. It is clear that the interplay between genetics, dietary habits and lifestyle determines a person’s risk to develop cardiovascular disease. While this relationship is less plastic in the case of monogenic or familial hypercholesterolemia (FH), the most common hypercholesterolemia cases are of polygenic nature and the interactions between genetic variation and environmentally induced responses are more plastic. Despite the nature of the pathology, the key challenge in hypercholesterolemia remains in the mismatch between genes involved in lipid metabolism and modern diet and a variety of lifestyle factors. The field of precision nutrition is focused on unravelling the factors that explain the interindividual variability in response to lifestyle and nutritional interventions. Latest advances in this area have explored how new applications of metabolomics, nutrigenomics and microbiota profiling could provide new avenues to successfully implement innovative precision nutrition approaches to identify health risks and implement preventative strategies to avoid disease. The current challenge remains to meaningfully translate these findings into clinically relevant pieces of information.