In cells, DNA typically consists of two antiparallel strands arranged in a double-helical structure, which is central to its fundamental role in storing and transmitting genetic information. In laboratories, however, DNA can be readily synthesized as a single-stranded polymer that can adopt many other types of structures, including some that have been shown to catalyze chemical transformations. These catalytic DNA molecules are commonly referred to as DNAzymes, or deoxyribozymes. Thus far, DNAzymes have not been found in cells, but hundreds of structural and functional variations have been created in the laboratory. This alternative catalytic platform has piqued the curiosity of many researchers, including those who seek to exploit them in potential applications ranging from analytical tools to therapeutic agents. In this review, we explore the unconventional role of DNA as a biologically inspired synthetic enzyme.