The availability of the assembled mouse genome makes possible, for the first time, an alignment and comparison of two large vertebrate genomes. We have investigated different strategies of alignment for the subsequent analysis of conservation of genomes that are effective for different quality assemblies. These strategies were applied to the comparison of the working draft of the human genome with the Mouse Genome Sequencing Consortium assembly, as well as other intermediate mouse assemblies. Our methods are fast and the resulting alignments exhibit a high degree of sensitivity, covering more than 90 percent of known coding exons in the human genome. We have obtained such coverage while preserving specificity. With a view towards the end user, we have developed a suite of tools and websites for automatically aligning, and subsequently browsing and working with whole genome comparisons. We describe the use of these tools to identify conserved non-coding regions between the human and mouse genomes, some of which have not been identified by other methods.