Our immune systems are capable of swift, potent action to clear microbial infections. Mechanisms for shutting off the immune response exist to maintain a critical balance between immune activation and dampening of the response after clearance. Dysregulation of these processes can lead to dangerous unchecked inflammatory responses and immunopathology. Defects in immune tolerance and recognition of self vs. non-self can cause autoimmunity and allergy. Early and late life periods both affect immune homeostasis, causing defects in the activation and control of the immune system. Research in these areas is focused on understanding these mechanisms of control and the ways in which host genetics, environment, microbial infection, and aging can affect this balance and cause tissue injury and autoimmunity.