During the last few years a novel role for previously known Zn(II) aminopeptidases has emerged, attracting a great deal of scientific interest to these molecules. Aminopeptidases appear now to play a key role in the last, yet crucial, proteolytic steps that generate small peptides for presentation onto MHC class I molecules so that the mature MHCpeptide complexes can be recognized by cytotoxic T-lymphocytes. In that context, ER aminopeptidases have been shown to strongly affect the adaptive immune response. ER aminopeptidase 1 (ERAP1) has been demonstrated to be a critical determinant of the immune response by generating mature antigenic epitopes from peptide precursors that arrive into the ER originating primarily from intracellular proteins degraded by the proteasome. At least one more related aminopeptidase, renamed ERAP2, appears to have important yet distinct roles in antigenic peptide generation. This review discusses recent findings that help to unravel the role of ER aminopeptidases in the immune response as well as the molecular properties that underlie this role. Determining the exact role and mechanism of action of these aminopeptidases will potentially provide tools for the pharmaceutical manipulation of the immune response on a subtle and qualitative level leading to novel therapeutic opportunities for the treatments of diseases ranging from autoimmunity to cancer.