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Cover Every mutation triggers an unknown cascade of molecular events, limiting our understanding of the fitness effect of genetic variations and thus, the impact of clinical sequencing. In this issue, a formal approach to this problem is presented. In the illustration, Sir Isaac Newton, an apple tree, and planetary orbits symbolize the laws of physics and math; Charles Darwin, the tree of life; and his original sketch and writings symbolize the laws of evolution. At the junction of the two trees, composed of nucleotide sequences, the Evolutionary Action equation unites these laws to express the genotype to phenotype relationship as a perturbation process. The terms of this equation can be evaluated and yield the fitness effect of genetic variations at the heart of evolution. (Cover illustration by Teng-Kuei Hsu. [For details, see Katsonis and Lichtarge, pp. 2050–2058.])