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Nucleic acids sensors of the innate immune system recognize various RNA and DNA structures during infection to induce transcription of interferon and pro-inflammatory cytokines and activation of inflammasomes. Cytosolic RNA is recognized by RIG-I and MDA5, while intracellular DNA is sensed among others by cGAS, AIM2, IFI16 and RNA polymerase III. The diversity of nucleic acid species produced during infection in the cytosol and nucleus and the limited chemical differences between self and non-self nucleic acids challenge the host’s innate pattern recognition system to ensure reliable sensing while avoiding immune activation by self nucleic acids. We review the molecular characteristics of intracellular nucleic acid sensor ligands, the structural basis of the binding preferences of the sensors, the identity and origin of immunostimulatory nucleic acid species during infection, the influence of intracellular localization of the sensor on immune activation, and the ability of viruses to use the ligand specificity of the sensors to evade recognition.