Except for the novel paired-end functionality and support for alignments in BAM format, many of the genomic comparisons supported by BEDTools can be performed in one way or another with available web-based tools. However, BEDTools offers several important advantages. First, it can read data from standard input and write to standard output, which allows complex set operations to be performed by combining BEDTools operations with each other or with existing UNIX utilities. Second, most of the tools can distinguish DNA strands when searching for overlaps, which allows orientation to be considered when interpreting paired-end mapping or RNA-seq data. Third, the use of BEDTools mitigates the need to interact with local or public instances of the UCSC Genome Browser or Galaxy, which can be a major bottleneck when working with large genomics datasets. Finally, the speed and extensive functionality of BEDTools allow greater flexibility in defining and refining genomic comparisons. These features allow for diverse and complex comparisons to be made between ever-larger genomic datasets.