There have been substantial improvements in statistical tools for assessing the evolutionary roles of mutation and natural selection from interspecific sequence data. The importance of having the rate at which a point mutation occurs depend on the DNA sequence at sites surrounding the mutation is now better appreciated and can be accommodated in probabilistic models of protein evolution. To quantify the evolutionary impact of some aspect of phenotype, one promising strategy is to develop a system for predicting phenotype from the DNA sequence and to then infer how the evolutionary rates of sequence change are affected by the predicted phenotypic consequences of the changes. Although statistical tools for characterizing protein evolution are improving, the list of candidate phenomena that can affect rates of protein evolution is long and the relative contributions of these phenomena are only beginning to be disentangled.