Two complex systems are emerging as being deeply involved in the control of energy metabolism. The intestinal microbiota, with its warehouse of genes, proteins and small molecules, i.e. the gut microbiome; and the endocannabinoid system, with its recent extension to a more complex signalling apparatus including more than one hundred lipid mediators and fifty proteins, i.e. the endocannabinoidome. Both systems can become perturbed following bad dietary habits and during obesity, thus contributing to exacerbating this latter condition and its consequences in both peripheral organs and the brain. Here we discuss some of the multifaceted aspects of the regulation and dysregulation of the gut microbiome and endocannabinoidome in energy metabolism and metabolic disorders, with special emphasis on the emerging functional interactions between the two systems. The potential exploitation of this new knowledge for the development of new pharmacological and nutritional approaches against obesity and its consequences is also briefly touched upon.