Besides their well known functions in storage and translation of information nucleic acids have emerged as a target of pattern recognition receptors that drive activation of innate immunity. Due to the paucity of building block monomers used in nucleic acids, discrimination of host and microbial nucleic acids as a means of self/foreign discrimination is a complicated task. Pattern recognition receptors rely on discrimination by sequence, structural features and spatial compartmentalization to differentiate microbial derived nucleic acids from host ones. Microbial nucleic acid detection is important for the sensing of infectious danger and initiating an immune response to microbial attack. Failures in the underlying recognitions systems can have severe consequences: thus, inefficient recognition of microbial nucleic acids may increase susceptibility to infectious diseases. On the other hand, excessive immune responses as a result of failed self/foreign discrimination are associated with autoimmune diseases. This review gives a general overview over the underlying concepts of nucleic acid sensing by Toll-like receptors. Within this general framework, we focus on bacterial RNA and synthetic RNA oligomers.