Nucleosides and their phosphorylated counterparts, nucleotides, are arguably the most versatile class of biomolecules. Most famously, they represent the backbone of life by encoding information as DNA and RNA. This code manages its own transcription, translation, replication, and proof-reading -an impressive feat for just five nucleosides and their derivatives. In addition, nucleosides play integral roles in cellular energy transfer systems and as cofactors for complex enzymatic transformations. It is therefore unsurprising that medicinal chemists were quick to recognize nucleoside analogues as ideal entry points for drug development campaigns to treat diseases which involve pathways hinging on the participation of nucleosides or nucleotides. The most striking examples of such diseases include cancers and viral infections, both of which depend on hijacking the cellular replication machinery for a fastpaced replication of genomic information. In many cases, administration of analogues of the natural nucleosides can inhibit key kinases or polymerases to either slow down cancer or viral proliferation, giving the innate immune system time to catch up. Alternatively, such an interference in the replication can introduce excessive mutations, leading to lower viability or even cell death. Given this pivotal role of nucleosides in medicinal and biological chemistry, it is easy to see why chemical methods to synthesize these compounds have attracted the interest of researchers for several decades and continue to do so in present times. However, nucleosides are less than trivial to make. Their relatively high content of heteroatoms makes many of them poorly soluble in common organic solvents, while their dense arrangement of functional groups (particularly on the ribosyl moiety) generally requires extensive protecting group schemes and demands a high degree of selectivity in key bond-forming steps. As such, truly "efficient" nucleoside synthesis is still considered an unmet challenge in organic chemistry, despite more than seven decades of research in the field. To circumvent many of the challenges encountered during conventional nucleoside synthesis, increased efforts have recently been made toward the development of biocatalytic methods. As a result of this trend, the greater enzyme family of nucleoside phosphorylases has witnessed a true renaissance. Natively, these enzymes perform the phosphorolysis of nucleosides, yielding the corresponding nucleobase and pentose 1-phosphate (Figure ). Since this transformation is fully reversible, they can also be employed for the synthesis of nucleosides, either from the corresponding sugar phosphate or by transglycosylation from a sacrificial glycosyl donor. Intriguingly, nucleoside phosphorylases exhibit perfect regio-and stereoselectivity over the glycosylation step and permit reactions with unprotected, readily available starting materials. Recent work from our group and others has elucidated the principles of thermodynamic control in these reaction systems and demonstrated the application of these enzymes in the synthesis of various pharmaceutically relevant nucleosides, including the anti-HIV drug islatravir and the anti-Covid19 drug molnupiravir, among others. Notwithstanding these advances, the widespread application of nucleoside phosphorylases in industrial manufacturing processes is still lacking. This stands in stark contrast to other established classes of enzymes such as lipases and alcohol dehydrogenases which have become a common sight in the pharmaceutical industry and beyond. We attribute this gap to three key challenges: i) the non-trivial downstream processing of enzymatic syntheses involving nucleosides, ii) the difficulties associated with large-scale preparation of these enzymes and their efficient (re-)use, and iii) their somewhat limited substrate scopes. This short review outlines these challenges, briefly discusses recent important advances, and highlights why future efforts will require a closer collaboration between traditionally distant scientific fields.