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It has long been recognized that certain sites within a protein, such as sites in the protein core or catalytic residues in enzymes, are evolutionarily more conserved than other sites. However, our understanding of rate variation among sites remains surprisingly limited. Recent progress to address this includes the development of a wide array of reliable methods to estimate site-specific substitution rates from sequence alignments. In addition, several molecular traits have been identified that correlate with site-specific mutation rates, and novel mechanistic biophysical models have been proposed to explain the observed correlations. Nonetheless, current models explain, at best, approximately 60% of the observed variance, highlighting the limitations of current methods and models and the need for new research directions.