Antisense oligonucleotides are invaluable reagents for the specific downregulation of gene expression. In the absence of a carrier, charged oligonucleotides (e.g., phosphorothioates) can interact with a large number of cell surface proteins, but tend to be internalized into the endosomal/lysosomal compartment. However, they can be successfully delivered to the nuclei of diverse cell types via the use of a wide variety of reagents, including cationic lipids, and cationic polyamines. Over the past several years, a more general understanding of the rules governing the interpretation of data derived from antisense experiments has been reached. These are discussed with emphasis on how to avoid some of the confounding features of this important, emerging technology.