Although 'self-nonself' and 'danger' theories have improved our understanding of the immune system, successful immunotherapy of cancer and many autoimmune diseases still remain far from reach. This indicates that our knowledge of how the immune system decides to respond effectively or ineffectively is limited. Emerging evidence suggest that decision-making during the immune response is not solely determined by 'nonself' entity of the antigen or damage-associated 'danger' signals. This article provides an overview of the 'self-nonself' and 'danger' models, and suggests that 'adaptation' signals are needed to guarantee immunological tolerance that has been observed during the immune response toward 'self', 'nonself' or even 'danger'. This should be facilitated by dynamic expression of adapting receptors (ARs) and adapting ligands on cells of the immune system and other somatic cells. Any alterations in the expression of ARs on certain tissues would result in tissue-specific autoimmune diseases or spontaneous regression of cancer. Identification of such ARs and their nominal adapting ligands could lead to the discovery of currently unknown receptors and their implications in the treatment of cancer, solid organ transplantation and autoimmune diseases.