Metabolic homeostasis is crucial for human survival. Hence ultimate health depends on proper functioning of the pathways that are involved in sensing and management of homeostasis. These metabolic systems are cohesively coupled and influenced by evolutionarily conserved pathways involving the stress signal pathways, pathogen -sensing and immune responses. This close functional and molecular integration of the stress, immune and metabolic systems are emerging as a crucial homeostatic mechanism, the dysfunction of which underlies many chronic metabolic diseases, including and not limited to addiction, cancer, type 2 diabetes and atherosclerosis. In this Review we provide an overview of several important networks that sense and manage nutrients and discuss how they integrate with the immune and inflammatory pathways to influence the physiological and pathological metabolic states in the body.