RNA-based therapies, including RNA molecules as drugs and RNA-targeted small 
molecules, offer unique opportunities to expand the range of therapeutic 
targets. Various forms of RNAs may be used to selectively act on proteins, 
transcripts, and genes that cannot be targeted by conventional small molecules 
or proteins. Although development of RNA drugs faces unparalleled challenges, 
many strategies have been developed to improve RNA metabolic stability and 
intracellular delivery. A number of RNA drugs have been approved for medical 
use, including aptamers (e.g., pegaptanib) that mechanistically act on protein 
target and small interfering RNAs (e.g., patisiran and givosiran) and antisense 
oligonucleotides (e.g., inotersen and golodirsen) that directly interfere with 
RNA targets. Furthermore, guide RNAs are essential components of novel gene 
editing modalities, and mRNA therapeutics are under development for protein 
replacement therapy or vaccination, including those against unprecedented severe 
acute respiratory syndrome coronavirus pandemic. Moreover, functional RNAs or 
RNA motifs are highly structured to form binding pockets or clefts that are 
accessible by small molecules. Many natural, semisynthetic, or synthetic 
antibiotics (e.g., aminoglycosides, tetracyclines, macrolides, oxazolidinones, 
and phenicols) can directly bind to ribosomal RNAs to achieve the inhibition of 
bacterial infections. Therefore, there is growing interest in developing 
RNA-targeted small-molecule drugs amenable to oral administration, and some 
(e.g., risdiplam and branaplam) have entered clinical trials. Here, we review 
the pharmacology of novel RNA drugs and RNA-targeted small-molecule medications, 
with a focus on recent progresses and strategies. Challenges in the development 
of novel druggable RNA entities and identification of viable RNA targets and 
selective small-molecule binders are discussed. SIGNIFICANCE STATEMENT: With the 
understanding of RNA functions and critical roles in diseases, as well as the 
development of RNA-related technologies, there is growing interest in developing 
novel RNA-based therapeutics. This comprehensive review presents pharmacology of 
both RNA drugs and RNA-targeted small-molecule medications, focusing on novel 
mechanisms of action, the most recent progress, and existing challenges.