Since humans and chimpanzees split from a common ancestor over 6 million years ago, human metabolism has changed dramatically. This change includes adaptations to a high-quality diet, the evolution of an energetically expensive brain, dramatic increases in endurance abilities, and capacity for energy storage in white adipose tissue. Human metabolism continues to evolve in modern human populations in response to local environmental and cultural selective forces. Understanding the nature of these selective forces and the physiological responses during human evolution is a compelling challenge for evolutionary biologists. The complex genetic architecture surrounding metabolic phenotypes indicates that selection probably altered allelic frequencies across many loci in populations experiencing adaptive metabolic change to fit their environment. A recent analysis supports this hypothesis, finding that classic selective sweeps at single loci were rare during the past 250 000 years of human evolution. Detection of selective signatures at multiple loci, as well as exploration of physiological adaptation to environment in humans, will require cross-disciplinary collaboration, including the incorporation of biological pathway analysis. This review explores the Thrifty Genotype Hypothesis, high-altitude adaptation, cold-resistance adaptation, and genetic evidence surrounding these proposed metabolic adaptations in an attempt to clarify current challenges and avenues for future progress.