Enzymes that operate on nucleic acid substrates are faced with the unusual situation where the substrate is much larger than themselves. Despite the potential to promote catalysis by utilizing the significant binding energy available through their interaction with substrate, ATP hydrolysis is frequently a part of the mechanism of these enzymes. The reasons for this have become clearer in recent years, and a surprising range of ways that these enzymes utilize the free energy of hydrolysis of ATP has been revealed. This review describes these different mechanisms in the context of the biochemical reactions that they support.