The innate immune system detects the presence of pathogens based on detection of non-self. In other words, most pathogens possess intrinsic differences that can distinguish them from host cells. For example, bacteria and fungi have cell walls comprised of peptidoglycan and carbohydrates (like mannans), respectively. Germline encoded pattern recognition receptors (PRRs) of the Toll-like receptor (TLR) and C-type lectin receptor (CLR) family have the ability to detect such unique pathogen associated features. However, some TLRs and members of the RIG-I-like receptor (RLR), NOD-like receptor (NLR), or AIM2-like receptor (ALR) family can sense pathogen invasion based on pathogen nucleic acids. Nucleic acids are not unique to pathogens, thus raising the question of how such PRRs evolved to detect pathogens but not self. In this chapter, we will examine the PRRs that sense pathogen nucleic acids and subsequently activate the inflammasome signaling pathway. We will examine the selective mechanisms by which these receptors distinguish pathogens from “self” and discuss the importance of such pathways in disease development in animal models and human patients.