Copper is a vital trace element required for normal growth and development of many organisms. To determine the roles for Ctr1 in hepatic copper metabolism and the contribution of the liver to systemic copper homeostasis, we have generated and characterized mice in which Ctr1 is deleted specifically in the liver. These mice express less than 10% residual Ctr1 protein in the liver and exhibit a small but significant growth retardation, which disappears with age. Hepatic copper concentrations and the activities of copper-requiring enzymes are reduced; however mild copper deficiency relative to Ctr1 protein deficit indicates compensatory mechanisms for copper metabolism. Copper concentrations of other organs did not altered, despite the defect in hepatic copper uptake. While biliary copper excretion is reduced, urinary copper concentration in these mice is higher than that of control mice. Our data indicates that Ctr1 plays a critical role in copper acquisition in the liver and, when Ctr1-expression is compromised, compensatory mechanisms facilitate copper uptake and/or retention in the liver and excretion of copper via urine.