The most important roles of proteinases in the immune system are found in apoptosis and major histocompatibility complex (MHC) class II-mediated antigen presentation. A variety of cysteine proteinases, serine proteinases, and aspartic proteinases as well as their inhibitors are involved in the regulation of apoptosis in neutrophils, monocytes, and dendritic cells, in selection of specific B and T lymphocytes, and in killing of target cells by cytotoxic T cells and natural killer cells. In antigen presentation, endocytosed antigens are digested into antigenic peptides by both aspartic and cysteine proteinases. In parallel, MHC class II molecules are processed by aspartic and cysteine proteinases to degrade the invariant chain that occupies the peptide-binding site. Proteinase activity in these processes is highly regulated, particularly by posttranslational activation and the balance between active proteinases and specific endogenous inhibitors such as cystatins, thyropins, and serpins. This article discusses the regulation of proteolytic processes in apoptosis and antigen presentation in immune cells and the consequences of therapeutic interference in the balance of proteinases and their inhibitors.