Metal-dependent nucleases are hydrolytic enzymes which perform phosphodiester cleavage of RNA and DNA. An entire host of nucleic acid enzymes possess this function, ranging from restriction enzymes and ribozymes to enzymes involved in DNA repair and recombination. While the advantages of metal ion-dependent mechanisms are often clear, exactly how these metal ions contribute to this reaction remains actively debated. The ways in which systems are both different and similar can provide important clues regarding mechanistic requirements. To this end, this review will examine current issues in this area within the broad context of protein and nucleic acid catalysts. These include important bioinorganic properties of metal ion cofactors, theories of nucleophile activation, the one vs multiple metal ion mechanism debate, metal ion movement during catalysis, and the coupling between conformation and catalysis. Approaches to these issues began with mutagenesis and x-ray crystallography, both of which have been used to identify important structural features. Recently, more interdisciplinary approaches have evolved. Quantitative thermodynamic studies of both metal ion and DNA binding have been invaluable to the discussion of proposed mechanisms. In a number of systems, a wide variety of spectroscopic, kinetic, and computational analyses are being increasingly utilized.