Three decades ago Gilbert posited that novel proteins arise by re‐shuffling genomic sequences encoding polypeptide domains. Today, with numerous genomes and countless genes sequenced, it is well established that recombination of sequences encoding polypeptide domains plays a major role in protein evolution. There is, however, less evidence to suggest how the novel polypeptide domains, themselves, arise. Recent comparisons of genomes from closely related species have revealed numerous species‐specific exons, supporting models of domain origin based on “exonization” of intron sequences. Also, (...) a mechanism for the origin of novel polypeptide domains has been proposed based on analyses of insertion‐based polymorphisms between orthologous genes across broad phylogenetic spectra and between allelic variants of genes within species. This review discusses these processes and how each might participate in the evolutionary emergence of novel polypeptide domains. BioEssays 29: 262–270, 2007. © 2007 Wiley Periodicals, Inc. (shrink)