Country food contributes significantly to the nutrition, health, and food security of Canadian Inuit communities. Despite this key role, the ongoing effects of colonization, climate warming, changes in food preferences, socio-economic challenges and concerns about contaminant exposure are leading to a rapid dietary transition. As western diets become more prevalent in the Canadian Arctic, health concerns, such as cardiometabolic disease, are on the rise. Advances in technology have allowed for a better understanding of the link between dietary practices and disease. The gut microbiome and the endocannabinoidome are two complex and interconnected systems which are heavily influenced by diet and which mediate many dietary implications for health. The development of new tools and model organisms is vital to allow for a more in-depth investigation of these systems as well as for the identification of early molecular biomarkers that are relevant to cardiometabolic disease pathogenesis. This chapter brings together a selection of results from the Sentinel North program that are increasing our understanding of the positive impacts of country food on the intestinal microbiota. It further examines the connections between diet and chronic diseases, investigates the role of the gut-brain axis and the endocannabinoidome in metabolic health, and sheds light on culturally adapted initiatives that tackle food and water security issues in collaboration with northern communities.