4-C-Modified nucleotides and oligonucleotides have been explored extensively recently. The motivations for these investigations drive from the development of new drugs to investigations of complex biological processes. This review covers the common strategies for the synthesis of 4-C-modified nucleosides that have been subsequently incorporated into oligonucleotides. After a brief depiction of two mainly followed routes for the generation of 4-C-modified nucleosides, the synthetic efforts of the modified nucleotides are grouped into those bearing hydrophobic or polar modifications. Subsequently strategies for the incorporation of the respective nucleotides into oligonucleotides by automated DNA synthesis are discussed.