This review discusses recent developments in the use of non-coding RNAs (ncRNAs) for the regulation of therapeutically relevant genes, with special focus on applications for the treatment of cardiovascular diseases. The interest in using ncRNAs as therapeutics has steadily increased since the discovery of RNA interference. During the last decade it has become evident that these RNAs, delivered either as oligos or expressed as small hairpin RNAs (shRNAs) from vectors, can either upregulate (transcriptional gene activation, TGA) or downregulate (transcriptional gene silencing, TGS) gene expression, typically inducing epigenetic changes in their target sites in the chromatin. Also, the important role of naturally occurring long non-coding RNAs (lncRNAs) has been recently discovered and will likely provide new insights into cardiovascular pathology and provide new treatment strategies based on the manipulation of their expression. In this review, we discuss the possibility of using ncRNAs for activating or silencing therapeutically relevant genes, such as VEGF-A, for the treatment of cardiovascular disease.