Since the discovery of the first natural ribozyme more than 20 years ago, it has become clear that nucleic acids are not only the static depository of genetic information, but also possess intriguing catalytic activity. The number of reactions catalyzed by engineered nucleic acid enzymes is growing continuously. The versatility of these catalysts supports the idea of an ancestral world based on RNA predating the emergence of proteins, and also drives many studies towards practical applications for nucleic acid enzymes.