Nucleoside analogs have proven highly successful in many pharmaceutical intervention strategies, and continued exploration of next generation structural motifs is required. Herein we discuss recent advances toward the chemical synthesis of heteroatom-modified nucleosides, where this is constituted by the chalcogens sulfur or selenium. Paying specific focus to the organic chemistry to incorporate these heteroatoms, we consider developments toward ribose ring oxygen and ring carbon replacements alongside chalcogen-modified heterobases.