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The neutral theory of molecular evolution has been instrumental in organizing our thinking about the nature of evolutionary forces shaping variation at the DNA level. More importantly, it has provided empiricists with a strong set of testable predictions and hence, a useful null hypothesis against which to test for the presence of selection. Evidence indicates that the neutral theory cannot explain key features of protein evolution nor patterns of biased codon usage in certain species. Whereas we now have a reasonable model of selection acting on synonymous changes in Drosophila, protein evolution remains poorly understood. Despite limitations in the applicability of the neutral theory, it is likely to remain an integral part of the quest to understand molecular evolution.