Mammalian promoters belong to two different categories in terms of base composition and DNA methylation. In humans and mice, approximately 60% of all promoters colocalize with CpG islands, which are regions devoid of methylation that have a higher G+C content than the genome average, while the rest have a methylation pattern and base composition indistinguishable from bulk DNA. Recent comparative studies between both organisms have refined our understanding of how CpG island promoters are organized in terms of protein-DNA interactions and patterns of expression. In addition, the finding that DNA replication initiates at CpG islands in vivo suggests that their distinctive properties could be a consequence of such activity and opens the possibility of a coordinated regulation of transcription and replication. These new data shed light on the origin and evolution of the CpG islands and should contribute to improving methods for promoter prediction in the human and mouse genomes.