Metal ions play important roles in biological processes. Despite the importance, our understanding of these metal ions is limited by the lack of a general method to obtain molecules that are selective for metal ions and convert these molecules into sensors for simultaneous imaging of metal ions with high spatial resolution. In addition, even though metal ions function through interactions with nucleic acids and proteins, many of these interactions remain poorly understood. To address these issues, we have used intro selection to obtain DNAzymes that are selective for not only a wide variety of metal ions (e.g., Li+, Na+, and K+, Mg2+, Mn2+, Zn2+, and UO22+) but also different oxidation state of the same metal ions (e.g., Fe2+, Fe3+, Cu+ and Cu2+). We have converted these DNAzymes into fluorescent sensors using a catalytic beacon approach that allows using different fluorophores for simultaneous imaging of metal ions in living cells, animal, and human tissues. In addition, taking advantage of recent advances of super-resolution imaging technologies such as fluorogenic DNA-PAINT, we have developed a Fluorogenic DNAzyme-PAINT technique, which fuses Fluorogenic DNA-PAINT with DNAzyme catalysis for super high-resolution imaging of labile metal ions. We have also developed novel methods to discover DNA, RNA, and proteins that interact with different metal ions in living cells. These results provide a strong foundation for spatial metallomics that will provide a comprehensive understanding of numerous metal ions in different biological processes.