The unexpected overlap between inflammatory and metabolic sensors and their downstream tissue responses indicates that inflammation plays a crucial role in the many complications of obesity. However, there remain many contradictions that have yet to be sorted out, such as how hypothalamic inflammation causes both obesity and anorexia, the role of the innate immune system in maintaining obesity, and the teleological reasons for obesity-dependent inflammation, among others. We feel that answering these questions requires approaches that allow a higher-resolution view of the different cellular mediators (e.g., macrophages, adipocytes, and lymphocytes) in fat that contribute to disease phenotypes. A second challenge will be to establish the differences and similarities between acute inflammatory signals and chronic activation of these pathways in diseases such as obesity. This temporal question is also a critical one for immunologists, who are employing systems biology approaches to tease out the dynamic network effects of transient versus persistent stimuli (119). These efforts provide opportunities to continue to revise our understanding of the nature of metainflammation in the hope of modifying it to prevent and treat disease.