microRNAs are small non-coding RNAs that regulate gene expression at the posttranscriptional level by either inhibiting mRNA translation or inducing mRNA degradation. These regulatory mechanisms occur in a sequence-specific manner through the direct binding of the microRNA to complementary reverse sequences in the 3' UTR of target mRNAs. The sequence-specific nature of microRNAs allows for the regulation of numerous target mRNAs, which often are related genes, resulting in the robust regulation of entire pathways. Previous studies have identified expression signatures of microRNAs during various pathological settings, including those of cardiovascular disease. As evident through gain- and loss-of-function studies in mice, it is apparent microRNAs play specific and essential roles during cardiac hypertrophy, fibrosis, angiogenesis, apoptosis, and contractility. The powerful effects of altering microRNA levels genetically have resulted in the rapid progression of oligo-based regulation of microRNAs as a new class of cardiovascular therapeutics. Here we summarize the current oligo-based technologies in use to regulate microRNA levels in vivo and how these technologies have been applied to multiple microRNAs during cardiovascular disease.