Membrane-bound and intracellular immune receptors respond to microbial pathogens by initiating signaling cascades that result in production of inflammatory cytokines and antimicrobial factors. These host responses need to be tightly regulated to prevent tissue damage and other harmful consequences of excessive inflammation. CARD-only proteins (COPs) and Pyrin-only proteins (POPs) are human- and primate-specific dominant negative inhibitors that modulate inflammatory and innate immune responses. In addition, several poxviruses encode POPs that interfere with inflammatory and host defense responses. COPs and POPs modulate inflammatory signaling at several checkpoints by sequestering key components of the inflammasome and NF-κB signaling cascades, thus hampering downstream signal transduction. Here, we review and discuss current understanding of the evolutionary history and molecular mechanisms by which roles of host- and virus-encoded COPs and POPs may regulate inflammatory and immune responses. In addition, we address their (patho)physiological roles and highlight topics for further research.