Zinc (Zn) is essential for normal cell structure and physiology. Its deficiency causes growth retardation, immunodeficiency, and neuronal degeneration. Zn homeostasis is tightly controlled through Zn transporters and metallothioneins, which regulate Zn concentration, its distribution in individual cells, and contribute to Zn signaling in cells. Zn intracellular signaling regulates immune reactions as well as hard and connective tissue development. Although many molecules involved in these processes have Zn-binding motifs, the molecular mechanisms of Zn's role have not been clarified. Recently, we and other groups demonstrated that Zn signaling plays diverse and specific roles in vivo and in vitro, in studies on the genetic knockout of Zn transporter functions. In this section, we discuss the impact of Zn signaling on the mast cell-mediated allergy response, T cell-mediated immune response, and development of hard and connective tissues. We also describe Zn signaling dysregulation as a leading health problem in allergy and immune response, and in skeletal and connective tissues' development.