Non-coding RNAs, including small interfering RNAs (siRNAs), microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), are gaining prominence in clinical medicine as potential diagnostics and therapeutics. With the introduction of 2nd generation synthetic chemistry, the stability of short double stranded RNAs (dsRNAs, siRNAs and miRNAs) has been dramatically enhanced, producing profound effects on target gene expression, and leading to the FDA approval in late 2018 of the first siRNA drug, Patisiran. This landmark decision paves the way for subsequent dsRNA drug development. We have applied 2nd generation synthetic chemistry to develop a novel miRNA mimic for the treatment of epithelial cancers. In addition, we have engineered a liver-specific version of the miRNA mimic to treat hepatocellular carcinoma (HCC). The application of these emerging technologies to the treatment of cancer has opened up a range of new opportunities.