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Next-generation sequencing technologies have a substantial impact on a broad range of biological applications. Like many other groups, we use these new technologies, especially SBS (Sequence-By-Synthesis), for deep profiling of small RNA molecules in plants. Small RNAs are 21-24 nucleotides in length and are known to play a major role in the activation of mRNAs and genomic DNAs. We have generated numerous SBS small RNA libraries; each can consist of more than three million signatures of more than 33 nucleotides in length. Here, we describe the challenges and our strategies to handle the very large quantity of small RNA data generated by these next-generation sequencing technologies.