Zinc is essential for cell proliferation thereby promoting growth and development, yet a rise of intracellular zinc is a leading cause of neuronal cell death in excitotoxic syndromes. While pervious studies have addressed mostly the structural role of zinc as a cofactor of numerous enzymes and zinc finger proteins, recent data suggest that zinc is acting as a signaling molecule. Despite the accumulating knowledge on the transporters, which are shown to maintain cellular and sub-cellular zinc homeostasis, the mechanisms by which they function are much less understood. Changes in extracellular or intracellular zinc trigger the activation of major signaling pathways, partially mediated by a specific zinc sensing receptor, which are linked to either cell growth or cell death. These proteins, which are regulated by zinc, will be the subject of this review. The major challenges in future studies will be to reveal the cellular network of zinc signaling and their links to cellular zinc homeostasis.