AbstractSelection acting on codon usage can cause patterns of synonymous evolution to deviate considerably from those expected under neutrality. To investigate the quantitative relationship between parameters of mutation, selection, and demography, and patterns of synonymous site divergence, we have developed a novel combination of population genetic models and likelihood methods of phylogenetic sequence analysis. Comparing 50 orthologous gene pairs from Drosophila melanogaster and D. virilis and 27 from D. melanogaster and D. simulans, we show considerable variation between amino acids and genes in the strength of selection acting on codon usage and find evidence for both long-term and short-term changes in the strength of selection between species. Remarkably, D. melanogaster shows no evidence of current selection on codon usage, while its sister species D. simulans experiences only half the selection pressure for codon usage of their common ancestor. We also find evidence for considerable base asymmetries in the rate of mutation, such that the average synonymous mutation rate is 20-30% higher than in noncoding regions. A Bayesian approach is adopted to investigate how accounting for selection on codon usage influences estimates of the parameters of mutation.