The fifteen years of utilizing RNAi present a surprise story, ranging from the unexpected discovery and publication of RNA interference in 1998, rewarded by the nobel prize in 2006, the introduction of synthetic short siRNAs for the specific gene silencing in mammalian cells in 2001, or the discovery of more than 1600 human microRNAs naturally regulating about one third of our genes. Therapeutic applications started amazingly fast and resulted in the first recent successes in therapy. Synthetic siRNAs are under evaluation for knocking down disease-associated target mRNAs, microRNA mimics for turning on or antagonists (antagomirs) for turning off microRNA activity. Modified oligonucleotides comprise a special class of therapeutics with a new chemical profile; the precise synthetic molecules are much smaller than protein or gene vector drugs, but they are larger than conventional drugs and thus cannot passively diffuse into their target cells. The main current strategies for solving the delivery problem are discussed. We now face the interesting question of alternative future directions: should oligonucleotide molecules be chemically further minimized into small drug-like chemical entities? Or should multiple RNAi molecules be wrapped up into larger virus-like nanoparticles for delivery? Biomaterials in therapeutic RNA interference, quo vadis?