The molecular apparatus that protects us against infection can also injure us by causing autoimmune or autoinflammatory disease. It now seems that at times, defects within the sensing arm of innate immunity contribute to diseases of this type. The initiation of an immune response is often microbe dependent and, in many cases, Toll-like receptor (TLR) dependent. Positive feedback loops triggering immune activation may occur when TLR signaling pathways stimulate host cells in an unchecked manner. Or, immune activation may persist because of failure to eradicate an inciting infection. Or on occasion, endogenous DNA may trigger specific immune responses that beget further responses in a TLR-dependent autoamplification loop. Specific biochemical defects that cause loop-related autoimmunity have been revealed by random germline mutagenesis and by gene targeting. We have also developed some insight into critical points at which feedback loops can be interrupted.