There are over two thousand proteins encoded by the human genome that bind zinc, where zinc binding is predicted to be essential for function. At the cellular level zinc is important for DNA synthesis, cell proliferation, differentiation, and apoptosis. Given the importance of Zn2+ in cell biology and human health, it is astounding that we still don’t understand the mechanisms of how Zn2+ levels and dynamics impact basic cellular functions and give rise to disease. Our lab has developed a suite of genetically encoded fluorescent sensors for Zn2+ and has used these sensors to quantify Zn2+ in different organelles in mammalian cells. Our results reveal that the labile Zn2+ pool is very low (hundreds of pM in the cytosol) but that cells experience Zn2+ dynamics and fluxes in response to cellular processes and environmental perturbations. Although the conventional view of Zn2+ in biology is that it is constitutively and stably bound to the proteins that comprise the zinc proteome, there is growing evidence that the proteome may sense and respond to Zn2+ dynamics in cells. This talk will focus on our discoveries that Zn2+ dynamics profoundly influence fundamental cellular processes such as gene expression, interactions between transcription factors and chromatin, and the mammalian cell cycle.