Because of the potent effector mechanisms of the immune system, the potential for self-destructive immune responses is especially high and many negative regulatory modalities exist to prevent excessive tissue damage. This Commentary places such regulatory mechanisms in the larger context of system organization on many scales. The sometimes counterintuitive nature of feedback control is discussed and a case is made for greater attention to quantitative spatiotemporal aspects of regulation, rather than limiting the discussion to the qualitative descriptions of pathways that dominate at present.