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Proto-oncogenes were first discovered as cellular counterparts of transforming retroviral oncogenes in the genomes of several vertebrate species. Evolutionary studies have revealed that proto-oncogenes have emerged early during phylogenesis, consistent with the finding that these genes possess crucial functions in such essential processes as cellular proliferation, differentiation and development. According to their biochemical and biological functions, these genes are divided into several functional classes, with the src-type protein tyrosine kinase and the receptor-protein tyrosine kinase gene families representing two of the most extensively studied proto-oncogene families. Furthermore, evolutionary studies have revealed the molecular mechanisms underlying the evolution of both src-type and receptor protein tyrosine kinases which can be traced back in phylogenesis by a defined set of criteria generally accepted to be essential for the evaluation of gene evolution, such as the exon/intron configuration. Changes in the molecular structure of proto-oncogenes can ultimately convert these genes into cellular oncogenes, which are associated with a variety of tumors. However, the first oncogenes to be identified were found in the genomes of transforming retroviruses, and today, these viruses are an attractive model system to study neoplastic transformation. One of the most significant, yet surprising discoveries was that these oncogenes are of non-viral origin, but were originally aquired through a process of illegitimate recombination with host genomic DNA. Taken together, phylogenetic studies, combined with structural and functional analyses, have significantly contributed to our understanding of the functions of proto-oncogenes and oncogenes in cellular proliferation, differentation, development and transformation.