The Basic Local Alignment Search Tool (BLAST) finds regions of local similarity between protein or nucleotide sequences. The program compares nucleotide or protein sequences to sequence in a database and calculates the statistical significance of the matches. This chapter first provides an introduction to BLAST and then describes the practical application of different BLAST programs based on the BLAST Quick Start mini-course (www.ncbi.nlm.nih.gov/Class/minicourses). In each example, emphasis is placed on practical step-by-step procedures, although relevant theory is also given where it affects the choice of BLAST program, parameters, and database.