CARD protein–BCL10–MALT1 signaling complexes (CBM complexes) are multiprotein signaling platforms that control immune and inflammatory pathways in most tissues. They can form self-organizing structures with MALT1 protease activity to regulate canonical NF-kB and MAPK pathways and the degradation of mRNA binding proteins and thereby provide two layers of inflammatory gene expression control. While these CBM-regulated mechanisms are essential for host defense and tissue homeostasis, numerous genetic alterations in CBM signaling components have been implicated in inherited and acquired immune-mediated diseases. Here we will discuss the regulation and signaling of CBM complexes, and their pathological functions in human immunodeficiency diseases and cancers of the immune system.