Complete genome doubling has long-term consequences for the genome structure and the subsequent evolution of an organism. It has been suggested that two genome duplications occurred at the origin of vertebrates (known as the 2R hypothesis). However, there has been considerable debate as to whether these were two successive duplications, or whether a single duplication occurred, followed by large-scale segmental duplications. In this article, we review and compare the evidence for the 2R duplications from vertebrate genomes with similar data from other more recent polyploids.