The current achievement of genome sequence projects of a dozen eukaryote organisms (including human genome) and the development of functional genomics are providing the basic knowledge required to utilize gene-specific reagents for both basic understanding of cell physiology and therapeutical development. The field of chemical genomics has the ambitious goal of designing molecules that could act selectively on every single gene or gene product in a cell and in vivo. The progress in oligonucleotide-based approaches will be the topic of this review, however, other nucleic acid- and SELEX-based approaches as well as high sequence-specific low molecular weight DNA-specific ligands will also be discussed.