The idea of sequence-specific gene silencing by synthetic oligonucleotides targeting mRNA is at least 40 years old, but it was only in the mid-1980s when technical advances made the chemical synthesis of oligonucleotides possible that practical steps could be taken toward its implementation. The result was a deluge of experimental data in a variety of systems [1], most of which employed the phosphorothioate (PS) backbone modification, and much of which was ultimately, and unfortunately, uninterpretable.