Dr. Beutler's major scientific work began with the discovery that G6PD deficiency was responsible for hemolysis in primaquine-sensitive individuals. Aware that G6PD is encoded by an X-linked gene, he began to ponder the mechanism of dosage compensation in mammals, which in turn led him to deduce and prove the principle of random embryonic X-chromosome inactivation. With this, he identified the first example of stochastic epigenetic silencing in humans, and showed that human females are mosaics of X-chromosome activity. This, in turn, led to the strongest evidence that neoplastic diseases are, for the most part, clonal. Indeed, he foresaw the importance of epigenetics years before most of the scientific community fully understood it.