Publisher Summary This chapter discusses the synthetic nucleic acids interfering with gene expression (SNAIGE), which are being developed as specific regulators of gene expression both for fundamental studies and/or for potential (medical) applications. Although straightforward in principle, the approach still faces many unknowns. Cell-free studies with model systems have helped one to learn much about the various modes through which oligonucleotides bind to their nucleic acids or protein targets. Increasing numbers of modifications allowing improved resistance toward nucleases or more efficient interaction with various targets have been devised and more will be forthcoming. A most exciting prospect has been enabled by synthetic material; the normal backbone of DNA has been replaced by a polyamide linkage, giving rise to “polyamide nucleic acid” that retains specificity in base recognition. Although a large number of genes have been successfully down-regulated in various biological systems. The tools of cell biology will help in solving pending questions, such as intracellular routing of SNAIGE, involvement of RNase H in their action, and accessibility of various sites in mRNAs, pre-mRNAs, or DNAs in their cellular environment. This helps to devise new tools on a more rational basis and to choose the best strategy in each case.