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By far the most widely used technique for detecting similarity between sequences of interest is the Basic Local Alignment Search Tool, or BLAST (Altschul et al. 1991). The widespread adoption of BLAST as a cornerstone technique in sequence analysis lies in its ability to detect similarities between nucleotide and protein sequences accurately and quickly, without sacrificing sensitivity. The original, standard family of BLAST programs is shown in Table 3.2, but in the time since its introduction many variations of the original BLAST program have been developed to address specific needs in the realm of pairwise sequence comparison, several of which will be discussed in this chapter.