Abstract The recent emergence of the thrifty phenotype as an explanation for metabolic efficiency has brought evolutionary perspectives on diabetes, as represented by the thrifty genotype, under scrutiny. However, the logic of natural selection along with evidence from non-human primates supports the role for energetic constraints in the evolution of metabolic efficiency, particularly in skeletal muscle physiology. Environmental fluctuation during human evolution would have provided selective pressures for the development of efficient skeletal muscle starting prenatally and continuing throughout the lifespan. Such mechanisms including, glucose transporters, mitochondrial gene expression, leptin receptors and uncoupling proteins, should be present in all humans, though some living populations may exhibit particular ‘thriftier’ alleles. A focus on physical activity and the factors underlying efficient muscle physiology has implications for prevention of diabetes in both developing and developed societies.