Nutritional epigenetics is a rapidly expanding field of research, and the natural modulation of the genome is a non-invasive, sustainable, and personalized alternative to gene-editing for chronic disease management. Genetic differences and epigenetic inflexibility resulting in abnormal gene expression, differential or aberrant methylation patterns account for the vast majority of diseases. The expanding understanding of biological evolution and the environmental influence on epigenetics and natural selection requires relearning of once thought to be well-understood concepts. This research explores the potential for natural modulation by the less understood epigenetic modifications such as ubiquitination, nitrosylation, glycosylation, phosphorylation, and serotonylation concluding that the under-appreciated acetylation and mitochondrial dependant downstream epigenetic post-translational modifications may be the pinnacle of the epigenomic hierarchy, essential for optimal health, including sustainable cellular energy production. With an emphasis on lessons learned, this conceptional exploration provides a fresh perspective on methylation, demonstrating how increases in environmental methane drive an evolutionary down regulation of endogenous methyl groups synthesis and demonstrates how epigenetic mechanisms are cell-specific, making supplementation with methyl cofactors throughout differentiation unpredictable. Interference with the epigenomic hierarchy may result in epigenetic inflexibility, symptom relief and disease concomitantly and may be responsible for the increased incidence of neurological disease such as autism spectrum disorder.