Abstract: RNA-based Therapeutics is an area of immense interest, research and development in the very recent years. Being able to modulate, target and utilize RNA in drug discovery and development offer new therapeutic avenues but also present new challenges. Antisense oligonucleotides have been explored as therapeutic agents since the 1980s and their rapid development has been applied to treat common, rare and nano-rare diseases. Here, I will discuss the different classes of these modalities (single-stranded and double-stranded), their mechanisms of action and unique challenges. I will focus on the very early steps of drug discovery process, and how critical these can be for the overall success of the development program. Target identification, validation and the importance of the optimal oligonucleotide design will be discussed.