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Viruses are obligatory intracellular parasites that require the host machinery to replicate. During their replication cycle, viral RNAintermediates can be recognized and degraded by different antiviral mechanisms that include RNAdecay, RNAinterference, and RNaseL pathways. As a consequence of viral RNAdegradation, infected cells can accumulate virus‐derived small RNAsat high levels compared to cellular molecules. These small RNAsare imprinted with molecular characteristics that reflect their origin. First, small RNAscan be used to reconstruct viral sequences and identify the virus from which they originated. Second, other molecular features of small RNAssuch as size, polarity, and base preferences depend on the type of viral substrate and host mechanism of degradation. Thus, the pattern of small RNAsgenerated in infected cells can be used as a molecular footprint to identify and characterize viruses independent on sequence homology searches against known references. Hence, sequencing of small RNAsobtained from infected cells enables virus discovery and characterization using both sequence‐dependent strategies and novel pattern‐based approaches. Recent studies are helping unlock the full application of small RNAsequencing for virus discovery and characterization. WIREs RNA2016, 7:824–837. doi: 10.1002/wrna.1361 For further resources related to this article, please visit the WIREs website.

RNA interference (RNAi) pathways utilize small non-coding RNAs (ncRNAs) to regulate diverse biological processes in eukaryotes. Different classes of small ncRNAs function through distinct RNAi pathways and the focus of this review will be on two of these: microRNAs (miRNAs) and small interfering RNAs (siRNAs). The siRNA pathway is triggered by viral infection and repetitive elements functioning as a defense system in eukaryotes. miRNAs, on the other hand, are encoded in the genome and regulate a myriad of biological processes such as embryonic development and tissue differentiation in plants and animals. These different small RNA pathways have great potential to be used as biomarkers of the biological processes they regulate. In this review, we describe the role RNAi pathways have in diverse pathological and physiological conditions and how the detection of specific small ncRNAs can be used as biomarkers for these conditions. We discuss other areas not yet explored for the use of small ncRNAs as biomarkers and review recent patents proposing to use small RNAs as biomarkers. These patents mainly include cases where changes in expression of miRNAs, individually or in groups, have been shown to correlate with disease or disease states, most commonly cancer.