It is no longer as difficult to determine genomic DNA sequences of uncultured bacteria as it once was, due to the development of DNA sequencing technology. It is likely that the number of whole-genome sequences of phytoplasmas will increase. In this chapter, two major strategies of whole-genome comparison studies, viz. gene content and orthologous protein sequence comparisons, are described. In general, horizontal gene transfer has greater influence on gene content-based phylogenetic analysis than orthologous protein sequence-based analysis. However, horizontal gene transfer has occurred rarely during the evolution of Mollicutes . Thus, the two phylogenetic topologies of the Mollicutes based on the two different strategies are similar.