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This book constitutes the refereed proceedings of the 6th RECOMB Comparative Genomics Satellite Workshop, RECOMB-CG 2008, held in Paris, France, in October 2008. The 19 revised full papers presented were carefully reviewed and selected from 48 initial submissions. The papers illustrate the crucial role of comparative genomics in understanding genome function and address a broad variety of aspects, ranging from the inference of evolution in genetic regulatory networks to the divergent fates of gene and genome duplication events and to the importance of new computational approaches to unraveling the structural evolution of genomes.