Phylogenetic reconstruction is a fast-growing field that is enriched by different statistical approaches and by findings and applications in a broad range of biological areas. Fundamental to these are the mathematical models used to describe the patterns of DNA base substitution and amino acid replacement. These may become some of the basic models for comparative genome research. We discuss these models, including the analysis of observed DNA base and amino acid mutation patterns, the concept of site heterogeneity, and the incorporation of structural biology data, all of which have become particularly important in recent years. We also describe the use of such models in phylogenetic reconstruction and statistical methods for the comparison of different models.