This review of sequence database searching aims to set out current practice in the area, in order to give practical guidelines to the experimental biologist. It describes the basic principles behind the programs and enumerates the range of databases available in the public domain. Of these, the most important are the equivalent DNA databases European Molecular Biology Laboratory (EMBL), GenBank and DNA Databank of Japan (DDBJ), and the protein databases Swiss-Prot and TrEMBL. The commonly used BLAST and FASTA algorithms are described in detail and alternative approaches mentioned briefly. Scoring matrices used to compare amino acid types during protein database searches are compared, with an emphasis on the PAM and BLOSUM series of observed substitution matrices.