The history and development of 4'-fluoro-nucleosides is discussed in this review. This is a class of nucleosides which have their origin in the discovery of the rare fluorine containing natural product nucleocidin. Nucleocidin contains a fluorine atom located at the 4'-position of its ribose ring. From its early isolation as an unexpected natural product, to its total synthesis and bioactivity assessment, nucleocidin has played a role in inspiring the exploration of 4'-fluoro-nucleosides as a privileged motif for nucleoside-based therapeutics.