The transition metal copper plays an essential role in many biological processes but is highly toxic in excess. Recent studies have characterized a highly conserved set of proteins that mediate cellular copper import, distribution, sequestration, utilization, and export. Nevertheless, the pathogenesis of copper overload and copper deficiency disorders is not well understood, and we are only beginning to comprehend the results of mild copper overload or deficiency in relation to nutritional uptake and common diseases at the population level. Technological advances open the possibility to dissect the complete genome for genetic variants predisposing to copper overload or depletion and for variations in gene expression generated by either reduced or excessive copper intake. We discuss the potential of integrated genome-wide applications to advance our knowledge of copper homeostasis and to develop molecular biomarker profiles as indicators of copper status.