This book constitutes the refereed proceedings of the Fourth International Symposium on Bioinformatics Research and Applications, ISBRA 2008, held in Atlanta, GA, USA in May 2008. The 35 revised full papers presented together with 6 workshop papers and 6 invited papers were carefully reviewed and selected from a total of 94 submissions. The papers cover a wide range of topics, including clustering and classification, gene expression analysis, gene networks, genome analysis, motif finding, pathways, protein structure prediction, protein domain interactions, phylogenetics, and software tools.