The immune system discriminates among multiple stimuli allowing some to provoke immune responses, leading to immunity, and preventing others from doing so, leading to tolerance. Immunological discrimination must emerge from processes that integrate contextual information from local tissue microenvironments to elicit appropriate responses to particular stimuli. Nevertheless, this network of integrated control mechanisms is not foolproof. Chronic infectious diseases, autoimmune disorders, and the pathologic state of tolerance displayed toward tumors all suggest a breakdown in these fundamental immunoregulatory processes. The potential to deliver improved clinical care to patients suffering from chronic inflammatory diseases and cancer provides considerable impetus to elucidate fundamental mechanisms underlying immune discrimination and regulation.