The nature of the relationship between an antigenic amino acid sequence and its capability to evoke an immune response is still an unsolved problem. Although experiments indicate that specific (dis)continuous amino acid sequences may determine specific immune responses, how immunogenic properties and recognition informations are mapped onto a non-linear sequence is not understood. Immunology has invoked the concept of self/nonself discrimination in order to explain the capability of the organism to selectively immunoreact. However, no clear, logical and rational pathway has emerged to relate a structure and its immuno-nonreactivity. It cannot yet be dismissed what Koshland wrote in 1990: "Of all the mysteries of modern science, the mechanism of self versus nonself recognition in the immune system ranks at or near the top". This chapter reviews the concept of self/nonself discrimination in the immune system starting from the historical perspective and the conceptual framework that underlie immune reaction pattern. It also introduces future research directions based on a proteomic dissection of the immune unit, qualitatively defined as a low-similarity sequence and quantitatively delimitated by the minimum amino acid requisite able to evoke an immune response, independently ofany, microbial or viral, "foreignness".