The CYRENE Project seeks to address the fundamental problem of determining de novo the function of regulatory sequence by developing the cis-Lexicon, a database of known cis-regulatory modules, the cis-Browser, a next-generation regulatory genome browser, and a library of tools for assisting in the annotation pipeline. The cis-Lexicon will be a comprehensive catalog of experimentally-validated gene regulatory knowledge, designed to be a foundation and benchmark for future prediction algorithms. The cis-Browser is a high-speed integrative genomics environment for viewing and annotating a variety of types of genomic information in the full genomic context. It is the result of two years of development and extension of the Celera Genome Browser. The cis-Browser is capable of displaying data from the cis-Lexicon, public online databases, and comparative genomics analyses. To aid annotators' entry of information into the cis-Lexicon, we are developing high-throughput tools for finding relevant literature and assisting in the extraction of correct information. We have also designed and implemented an efficient algorithm for mapping Solexa reads to a genome while allowing for up to four mismatches. This mapper has been used to map reads from Lytechinus variegatus (which has not been completely sequenced) to the Strongylocentrotus purpuratus genome, detecting conserved regions which may have a regulatory function. Our team of annotators has entered the cis-regulatory modules of nearly 200 genes into the cis-Lexicon and this number continues to grow. Early releases of the cis-Browser have been successfully used at the Davidson Lab at Caltech to aid in experimental design and analysis, and preparations for a public release of the cis-Lexicon and cis-Browser are underway.