Zinc ion (Zn2+) is essential for life; its deficiency in the human body could cause stunted growth, anemia and susceptibility to infection. The Zn transporter ZIP8 (also known as SLC39A8) is an important Zn2+ importer; aberrant Zn2+ influx mediated by ZIP8 can lead to the pathogenesis of osteoarthritis and inflammatory diseases. ZIP8 also mediates the cellular uptake of divalent metal ions including iron, manganese, and the toxic heavy metal cadmium. Individuals with SLC39A8 mutations and transgenic mouse models are starting to reveal the critical role that this gene plays in embryonic development and the metabolism of essential metal ions. Here we summarize our current understanding of ZIP8's function and regulation, at both the molecular and biological levels. We also review the association of ZIP8 with various diseases and its linkage with complex disorders like obesity, hypertension, and schizophrenia as revealed by several large genome-wide association studies.