Previous chapters explored what biological sequences are, how they are aligned, and how similarity is measured. This chapter discusses BLAST itself. What is BLAST? The simple answer is that it is a set of programs that search sequence databases for statistically significant similarities. The details of how BLAST searches for similarities aren't so easily answered. Searching requires multiple steps and many controlling parameters. Understanding the theoretical framework will help you design and interpret BLAST experiments, and give you a foundation for troubleshooting when your search produces unexpected results.