Inflammation and lipid signaling are intertwined modulators of homeostasis and immunity. In addition to the extensively studied eicosanoids and inositol phospholipids, emerging studies indicate that many other lipid species act to positively and negatively regulate inflammatory responses. Conversely, inflammatory signaling can significantly alter lipid metabolism in the liver, adipose tissue, skeletal muscle, and macrophage in the context of infection, diabetes, and atherosclerosis. Here, we review recent findings related to this interconnected network from the perspective of immunity and metabolic disease.