The aim of this review is to outline modern methods for synthesizing natural oligodeoxynucleotides and certain analogues that may be inhibitors of gene expression. As a consequence, several DNA chemical synthesis methodologies such as the phosphate diester and phosphate triester approaches, which are now primarily only of historical interest, will not be discussed, even though they contributed significantly towards solving many important biological problems (Khorana et al., 1966, 1972; Caruthers, 1980; Itakura et al., 1984). Instead the more recent methodologies, which involve phosphorus(III) chemistry, will be emphasized (the phosphite triester and H-phosphonate approaches). There are two reasons. First, these chemistries are compatible with polymer-supported DNA synthesis procedures — a method that is uniquely suited to automation. Second, since phosphorus(III) intermediates can be oxidized to a large number of analogues, these approaches offer a versatility for modifying DNA that is not available with the earlier-developed methodologies. There are, however, certain analogues having potential as inhibitors of gene expression that are currently prepared using phosphorus(V) chemistry. The synthesis of these analogues will also be outlined.