RNA modulation has become a promising therapeutic approach for the treatment of several types of disease. The emerging field of noncoding RNA-based therapies has now come to the attention of cardiovascular research, in which it could provide valuable advancements in comparison to current pharmacotherapy such as small molecule drugs or antibodies. In this review, we focus on noncoding RNA-based studies conducted mainly in large-animal models, including pigs, rabbits, dogs, and nonhuman primates. The obstacles and promises of targeting long noncoding RNAs and circRNAs as therapeutic modalities in humans are specifically discussed. We also describe novel ex vivo methods based on human cells and tissues, such as engineered heart tissues and living myocardial slices that could help bridging the gap between in vivo models and clinical applications in the future. Finally, we summarize antisense oligonucleotide drugs that have already been approved by the Food and Drug Administration for targeting mRNAs and discuss the progress of noncoding RNA-based drugs in clinical trials. Additional factors, such as drug chemistry, drug formulations, different routes of administration, and the advantages of RNA-based drugs, are also included in the present review. Recently, first therapeutic miRNA-based inhibitory strategies have been tested in heart failure patients as well as healthy volunteers to study effects on wound healing (NCT04045405; NCT03603431). In summary, a combination of novel therapeutic RNA targets, large-animal models, ex vivo studies with human cells/tissues, and new delivery techniques will likely lead to significant progress in the development of noncoding RNA-based next-generation therapeutics for cardiovascular disease.