Over the last two decades, small activating RNAs (saRNAs) have quickly moved from discovery to clinical trials. Characterized as 20 nucleotide long, double stranded RNA, saRNAs have the unique ability to increase gene transcription at the chromatin level. This therapeutic modality has great potential as a safe and redosable alternative to gene therapy by increasing target protein expression without changing the genetic sequence. We describe the successful in vivo saRNA delivery vectors and found that similar to small interfering RNA (siRNA) and mRNA targeting tissues outside the liver works best at the end of a needle. We highlight nanoparticle vectors and RNA-conjugates, where some success has been reported for non-hepatic delivery of saRNA-aptamers.