Our increasing understanding of the regulatory mechanisms involved in the pathogenesis of disease is opening up opportunities for therapeutic intervention. To tackle the unmet disease burden, the last decade has seen the emergence of gene-targeting small-molecule nucleic acid-based strategies, such as antisense oligodeoxynucleotides, ribozymes, small interfering RNA and DNAzymes. DNAzymes represent promising candidates for drug therapy in a wide range of diseases, such as cancer and cardiovascular disorders. This brief review will discuss recent developments in DNAzymes and their therapeutic potential.