MALT1 paracaspase links signaling cascades emanating from adaptive or innate immune receptors to the canonical NF-κB pathway. Now, Jaworski et al () investigate the physiological role of MALT1 protease activity in mice. Besides the expected requirement of MALT1 activity for immune activation, the study unveils a novel function for MALT1 activity for the development of peripheral tolerance. Thus, MALT1 protease can act immunogenic or tolerogenic, and this interplay will be highly relevant for the clinical development of MALT1 inhibitors. The unexpected finding that the NF-κB-regulating MALT1 protease can act either immunogenic or tolerogenic in vivo bears important implications for the clinical development of MALT1 inhibitors.