This book constitutes the thoroughly refereed post-proceedings of two joint RECOMB 2005 satellite events - the First Annual Workshop on Systems Biology, RSB 2005, and the Second Annual Workshop on Regulatory Genomics, RRG 2005, held in San Diego, CA, USA in December 2005.The 21 revised full papers presented were carefully reviewed and selected for inclusion in the book. The papers address a broad variety of topics in systems biology and regulatory genomics including inference of gene regulatory and protein signaling networks, model prediction of drug mechanism, pathway mapping and evolution in protein interaction networks, multi-scale methods which bridge abstract and detailed models, systematic design of genome-scale experiments, modeling and recognition of regulatory elements, identification and modeling of cis-regulatory regions, modeling the structure and function of the regulatory region, and comparative genomics of regulation.