During microbial infection and tissue injury, nucleic acids and their metabolites, such as nucleotides, nucleosides and uric acids, can be released from dying host cells and may modify immune responses. These nucleic acids and/or their metabolites are in fact recognized by specific host receptors, such as Toll-like receptors (TLRs), RIG-like receptors (RLRs) and NOD-like receptors (NLRs), purinergic receptors such as P2X and P2Y receptors, and adenosine receptors such as A2A receptors. The resultant responses may vary depending on the balance between immune responses to and metabolism of nucleic acids, thereby contributing not only to the host defense, but also to the homeostatic clearance of host dying cells, or even to deleterious autoimmune diseases.