An ongoing issue in mass spectrometry is the time it takes to search DNA sequences with MS/MS peptide fragments (see, e.g., Choudary et al., Proteomics 2001; 1: 651-667.) Search times are far longer than spectra acquisition time, and parallelization of search software on clusters requires doubling the size of a conventional computing cluster to cut the search time in half. Field programmable gate arrays (FPGAs) are used to create hardware-accelerated algorithms that reduce operating costs and improve search speed compared to large clusters. We present a novel hardware design that takes full spectra and computes 6-frame translation word searches on DNA databases at a rate of approximately 3 billion base pairs per second, with queries of up to 10 amino acids in length and arbitrary wildcard positions. Hardware post-processing identifies in silico tryptic peptides and scores them using a variety of techniques including mass frequency expected values. With faster FPGAs protein identifications from the human genome can be achieved in less than a second, and this makes it an ideal solution for a number of proteome-scale applications. Copyright 2005 John Wiley & Sons, Ltd.