Basic Local Alignment Search Tool (BLAST) is one of the most heavily used sequence analysis tools available in the public domain. There is now a wide choice of BLAST algorithms that can be used to search many different sequence databases via the BLAST web pages (http://www.ncbi.nlm.nih.gov/BLAST/). All the algorithm-database combinations can be executed with default parameters or with customized settings, and the results can be viewed in a variety of ways. A new online resource, the BLAST Program Selection Guide, has been created to assist in the definition of search strategies. This article discusses optimal search strategies and highlights some BLAST features that can make your searches more powerful.