One long-standing research focus in evolutionary genomics is trying to resolve how biological variables (expression, essentiality, protein-protein interaction, structural stability, etc.) determine the rate of protein evolution. While these studies have considerably deepened our understanding of molecular evolution, many issues remain unsolved. In this opinion article, after having a brief survey of literatures, we establish relationships between model parameters of molecular evolution and genomic variables, based on which, most-observed genomic correlations and confounds can be explained by model parameter combinations under different conditions, which include the strength of stabilizing selection, mutational variance, expression sufficiency, gene pleiotropy, as well as the effective population size. We suggest that the problem to discern biological variable(s) that may determine the rate of protein evolution can be tackled at two levels. The first level, as discussed here, is to demonstrate how the model of molecular evolution can predict potential genomic correlations under various conditions. And the second level is to estimate genome-wide variations of model parameters (or combinations) that help to identify canonical biological variables that may underlie the rate variation among genes that ranges up to at least three magnitudes.