The genome of the nematode Caenorhabditis elegans was the first animal genome sequenced. Subsequent sequencing of the Caenorhabditis briggsae genome enabled a comparison of the genomes of two nematode species. In this chapter, we describe the methods that we used to compare the C. elegans genome to that of C. briggsae. We discuss how these methods could be developed to compare the C. elegans and C. briggsae genomes to those of Caenorhabditis remanei, C. n. sp. represented by strains PB2801 and CB5161, among others (1), and Caenorhabditis japonica, which are currently being sequenced.