It is likely that the heritability of T2DM goes beyond simple genetic markers and involves epigenetic mechanisms. Neels Thrifty Gene Hypothesis was expanded by Chakravarthy to include metabolic cycling and the dissonance between our stone-age genes with a space-age lifestyle. Further modifications of this hypothesis continued after recent developments in evolutionary and epigenetic research. At the molecular forefront, energy-sensing signaling pathways in T2DM, such as PGC1α, AMPK, O-GlcNAc and most recently SIRT1 have been shown to play key roles in oxidative stress, mitochondrial dysfunction, inflammation and glucolipotoxicity, which are the hallmarks of insulin resistance and T2DM, Furthermore, SIRT1, PGC1α and O-GlcNAc also regulate gene expression and may play a role in the epigenetic machinery, thus providing an explanation to how metabolism switches to either a thrift or spend mode depending on food availability. Separate evidence on adaptations to exercise further links T2DM with decreased physical activity. In this review, the major findings from the epigenetic, epidemiological, molecular and clinical forefronts are integrated and unified as a coherent hypothesis for the etiology and pathogenesis of T2DM. It is an opportune time to start connecting the dots to provide the much needed basis for a better understanding of T2DM and a more targeted approach to drug development and treatment strategies.