In fungi, cell fusion between genetically unlike individuals triggers a cell death reaction known as the incompatibility reaction. In Podospora anserina, the genes controlling this process belong to a gene family encoding STAND proteins with an N-terminal cell death effector domain, a central NACHT domain and a C-terminal WD-repeat domain. These incompatibility genes are extremely polymorphic, subject to positive Darwinian selection and display a remarkable genetic plasticity allowing for constant diversification of the WD-repeat domain responsible for recognition of non-self. Remarkably, the architecture of these proteins is related to pathogen-recognition receptors ensuring innate immunity in plants and animals. Here, we hypothesize that these P. anserina incompatibility genes could be components of a yet-unidentified innate immune system of fungi. As already proposed in the case of plant hybrid necrosis or graft rejection in mammals, incompatibility could be a by-product of pathogen-driven divergence in host defense genes.