Antisense DNA and RNA are valuable tools to inhibit expression of a target gene in a sequence-specific manner. These molecules are not only widely used for gene functional study but also for therapeutic purpose. The strategy for therapeutics is attributed to its specific inhibition of gene expression of pathogens or disease-causing genes. Three types of anti-mRNA strategies can be distinguished, including antisense oligodeoxynucleotide (AODN), nucleic acid enzymes, and double-stranded small interfering RNA (siRNA). In this article we overview the basic principles of AODN and siRNA and then focus on their potential applications in antiviral therapy including our own data on coxsackieviral infection, a common pathogen of human myocarditis. In addition, we also briefly discuss the problems and difficulties in these drug developments, which need to be overcome to achieve the final goal in clinical application.