The computational power needed for searching exponentially growing databases, such as GenBank, has increased dramatically. Three different implementations of the most widely used sequence alignment tool, known as BLAST (Basic Local Alignment Search Tool), are studied for their efficiency on nucleotide-nucleotide comparisons. The performance of these implementations are evaluated using target databases and query sequences of varying lengths and number of entries constructed from human genomic and EST sequences. In general, WU BLAST was found to be most efficient when the database and query composition are unknown. NCBI BLAST appears to work best when the database contains a small number of sequences, while mpiBLAST shows the power of database distribution when the number of bases per target database is large. The optimal number of compute nodes in mpiBLAST varies depending upon the database, yet in the cases studied, remains surprisingly low.