Gene silencing techniques are gaining increasing popularity in the literature, both as a tool for unravelling gene function and to potentially deliver therapeutic benefit, especially in the context of cardiovascular disease. Gene‐specific catalytic DNA molecules, or DNAzymes, have shown promise in ameliorating the effects of myocardial ischaemia reperfusion injury and in‐stent restenosis in various animal models, demonstrating that these agents may be useful in a clinical setting. A review of the recent advances in the use of DNAzymes in treating cardiovascular disease is therefore essential given the increasing clinical burden of cardiovascular disease worldwide. We have thus sought to firstly provide background into the construct and mechanism of action of DNAzymes, with a discussion of recent improvements in design. Secondly, we have examined the effects of DNAzyme‐mediated gene inhibition inin vitrostudies of both endothelial and smooth muscle migration and proliferation, as well asin vivomodels of acute myocardial infraction and neointima formation. Lastly we compare DNAzymes with other gene silencing tools and discuss issues involved in successfully delivering these drugs in a clinical setting.British Journal of Pharmacology(2008)154, 741–748; doi:10.1038/bjp.2008.145; published online 5 May 2008