Nucleic acid enzymes (NAEs) are catalytically active RNA and DNA molecules. NAEs with RNA-cleaving activity are most extensively studied for applications in analytical chemistry, gene therapy and nanotechnology. Most NAEs require metal ions for activity. From a biochemical standpoint, these NAEs are reminiscent of metalloprotein enzymes with metal binding sites. While most NAEs require a single metal for the reaction, more and more recent examples have emerged that use two or even three metals for the reaction. The metal binding profile is sharper for these NAEs if they use the same metal ion due to cooperativity. Detailed studies have indicated examples of lanthanide and Ca2+ binding DNAzymes, where the metals interact with the non-bridging oxygen atoms in the scissile phosphate, and these DNAzymes often have a very strong thio effect that cannot be rescued by adding thiophilic metals. Another type uses multiple different metals, where one metal interacts with the scissile phosphate and the other binds to the catalytic loop for allosteric interactions. Such allosteric NAEs can also be obtained via rational design or intentional selection based on existing NAEs. These multi-metal NAEs might be useful as logic gates with metal ions as inputs. In this article, we review different types of NAEs based on their use of metal ions. The NAEs reviewed include ribozymes, DNAzymes and rationally designed aptazymes. Finally, their emerging applications are discussed, and some future research opportunities are proposed.