Darwin's "On the Origin of Species"(1859) successfully argued for the reality of organic evolution (his “descent with modification”), but he failed to convince that the mechanism was natural selection operating on the inherited variation of traits existing within a population of sexually reproducing organisms. Throughout the next several decades other theories were proposed claiming that intergenerational transformation was instead due to Lamarckian-like inheritance of acquired characteristics, large-scale mutations inducing instant new species, or internal factors acting independently and driven by quasi non-material forces. Only with the discovery of chromosomes and genes, and the formulation of the foundation of modern genetics in the early part of the last century, did it become clear that Darwinian natural selection could serve as the chief explanation for the temporal transformation of life. Much of this research came to Simpson's attention in the mid-1930s, particularly seminal papers by R.A. Fisher (esp. 1930), Sewall Wright (esp. 1931), and J.B.S. Haldane (esp. 1932), and in particular T. Dobzhansky's book, "Genetics and the Origin of Species" (1937).

By virtue of Simpson's heavy dose of biology while a graduate student at Yale, his institutional contact with biologically oriented colleagues at the American Museum of Natural History – Osborn, Matthew, and Gregory – and his own deep study of mammalian paleontology, he was able to extend the “New Genetics” into a dynamic reading of the fossil record that went beyond the more usual descriptive morphology and taxonomy of the day. Simpson's "Tempo and Mode in Evolution" (written from 1938 to 1942, published in 1944), together with Dobzhansky's book, Ernst Mayr's "Systematics and the Origin of Species," (1942) and G. Ledyard Stebbin's, "Variation and Evolution of Plants" (1950), were the pillars of the “modern evolutionary synthesis,” a phrase coined after Julian Huxley‘s, "Evolution: the Modern Synthesis" (1942).