Pattern recognition receptors (PRRs) expressed by both innate immune and non-immune cells are essential for detecting invading pathogens and initiating the innate and adaptive immune response. There are multiple families of PRRs including the membrane-associated Toll-like receptors (TLRs) and C-type lectin receptors (CLRs), and the cytosolic NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), and AIM2-like receptors (ALRs). All of these receptors are activated by specific pathogen-associated molecular patterns (PAMPs) present in microbial molecules, or by damage-associated molecular patterns (DAMPs) exposed on the surface of, or released by, damaged cells. In most cases, ligand recognition by PRRs triggers intracellular signal transduction cascades that result in the expression of pro-inflammatory cytokines, chemokines, and antiviral molecules. In contrast, some NLRs and ALRs oligomerize to form multiprotein inflammasome complexes that serve as platforms for the cleavage and activation of Caspase-1. Caspase-1 promotes the maturation and secretion of IL-1 beta and IL-18, which further amplifies the pro-inflammatory response. Crosstalk between different receptors may also play a role in either enhancing or inhibiting the immune response since a single pathogen can simultaneously activate multiple PRRs. Therefore, tight regulation of PRR signaling is required in order to eliminate infectious pathogens and at the same time, prevent aberrant or excessive PRR activation, which can lead to the development of inflammatory and autoimmune disorders.