In vitro–transcribed mRNA (IVT mRNA) is emerging as a new class of drug that has the potential to play a role in gene therapy that once was envisioned for DNA.1 Although first described as a therapeutic in 1992,2 IVT mRNA’s immunogenicity prevented its development for protein replacement therapies. However, this problem was recently solved by the introduction of modified nucleosides into the IVT mRNA.3 In this issue of Molecular Therapy, Thess and colleagues report an alternative method for generating nonimmunogenic IVT mRNA that avoids the use of modified nucleosides.4 They demonstrate that sequence engineering of the mRNA and purifying it with high performance liquid chromatography are sufficient to avoid immune activation and to achieve high levels of translation of the encoded protein both in vitro and in vivo.