The FASTA package provides a comprehensive set of similarity searching programs, similar to those provided by the BLAST package, and some additional programs for searching with short peptides and oligonucleotides that are not provided by BLAST. The FASTA programs work with a wide variety of database formats, including mySQL sequence databases. FASTA provides very accurate statistical significance estimates, and is more sensitive than BLASTN when comparing DNA sequences. These protocols describe how to use the FASTA programs to characterize protein and DNA sequences, using protein:protein, protein:DNA, and DNA:DNA comparisons.