Autoimmune disease is characterized by clinical symptoms mediated by adaptive (T cell and B cell) immune reactions towards autoantigen-expressing tissue. Here we discuss that autoimmune disease is often preceded by autoreactivity, meaning the priming of autoantigen-specific immune cells without relevant tissue damage. Recent experimental evidence has demonstrated that both the induction of autoreactivity and the conversion into autoimmune disease is controlled by the activation of the nonspecific innate immune system. Also, the "inflammatory status" of the target organ critically influences the onset of overt autoimmune disease.