 Small interfering RNAs, CERNAs, and microRNAs, MyRNAs, discovered over two decades ago, are now coding RNAs with important roles in gene regulation that have recently been investigated as novel therapeutic agents for various disorders. While both CERNAs and MyRNAs share many similarities, such as being short duplex RNA molecules that target messenger RNA, mRNA, their mechanisms of action and clinical applications are distinct. The major difference between them is that CERNAs have only one mRNA target, while MyRNAs have multiple targets. This review compares therapeutic CERNAs and MyRNAs in terms of their mechanisms of action, physical chemical properties, delivery, and clinical applications, as well as the challenges in developing both classes of RNA as therapeutics. This article was authored by Jenny K. W. Lam, Michael Y. T. Chao, Yu Zhong, and others. Thank you for watching!