Immunity and metabolism are tightly coupled, but the underlying mechanistic connections and biological roles for coupling are not well understood. This talk will discuss how systems pathway biology approaches have helped reveal an altered immune homeostatic set-point in early life infections that exacerbates myeloid regulatory signalling and sugar-lipid metabolism with a concomitant inhibition of lymphoid responses. By integrating immune and metabolic pathways we have inferred a novel immune-metabolic axis that accurately predicts sepsis in neonates and infants. A causal physiological link between immunity and metabolism has also been gained through systematic pathway biology investigations of infected macrophages that have led to discovering the existence of the ‘molecular wires’ that link the immune interferon response to host defense effector functions mediated via regulating the metabolic flux and secondary metabolites of the mevalonate-cholesterol biosynthesis pathway.