Subfamily II of the solute-carrier (Slc)39a family contains three highly conserved members (ZIPs 1 to 3) that share a twelve amino acid signature sequence present in the putative fourth transmembrane domain and function as zinc transporters in transfected cells. The physiological significance of this genetic redundancy is unknown. Herein, we report that the complete elimination of all three of these Zip genes, by targeted mutagenesis and cross-breeding mice, causes no overt phenotypic effect. When fed a zinc-adequate diet, several indicators of zinc status were indistinguishable between wild-type and triple-knockout mice; including embryonic morphogenesis and growth, alkaline phosphatase activity in the embryo, and ZIP4 protein in the visceral yolk sac and initial rates (30 min) of accumulation/retention of ⁶⁷Zn in liver and pancreas. When fed a zinc-deficient diet, embryonic membrane-bound alkaline phosphatase activity was reduced to a much greater extent and 80% of the embryos in the triple-knock mice developed abnormally compared to 12% of the embryos in wild-type mice. During zinc deficiency, the accumulation/retention (3 hr) of ⁶⁷Zn in the liver and pancreas of weanlings was significantly impaired in the triple-knockout mice compared to wild-type mice. Thus, none of these three mammalian Zip genes apparently plays a critical role in zinc homeostasis when zinc is replete, but they play important, non-compensatory roles when this metal is deficient.