Gene-silencing strategies based on catalytic nucleic acids have been rapidly developed in the past decades. Ribozymes, antisense oligonucleotides and RNA interference have been actively pursued for years due to their potential application in gene inactivation. Pioneered by Joyce et al., a new class of catalytic nucleic acid composed of deoxyribonucleotides has emerged via an in vitro selection system. The therapeutic potential of these RNA-cleaving DNAzymes have been shown both in vitro and in vivo. Although they rival the activity and stability of synthetic ribozymes, they are limited by inefficient delivery to the intracellular targets. Recent successes in clinical testing of the DNAzymes in cancer patients have revitalized the potential clinical utility of DNAzymes.