Large synthetic nucleic acid libraries are becoming increasingly critical to many fields of research. Originally largely confined to DNA microarrays for transcriptome analysis and genotyping, emerging applications in synthetic biology, nanobiotechnology, nucleic acid therapeutics, and information technology (i.e., storage of digital data in DNA ) require inexpensive on-demand synthesis not just of DNA, but also of RNA, chemically modified nucleosides (sugar, nucleobase or backbone modifications), and oligonucleotides incorporating structural modifiers, fluorescent or affinity labels, and degenerate nucleobases. The chemical synthesis of nucleic acids is based on the robust and efficient phosphoramidite chemistry developed by Caruthers and Beaucage . The ability to easily synthesize nucleic acids provided by this chemistry is among the most important advances in biological chemistry of the last century and constitutes a core technology underlying much of modern biological research. Consisting of repeated cycles containing coupling, oxidation, and deblocking steps, the chemistry allows for fully automated synthesis using phosphoramidite building blocks. The shared chemistry allows most nucleic acids to be synthesized using similar cycles, and for different nucleic acid types to be combined within an oligonucleotide to yield, for example, DNA-RNA chimeric sequences, or oligonucleotides labeled via fluorescent phosphoramidites. In their original form, the phosphoramidites are equipped with an acid-labile dimethoxytrityl (DMTr) 5'-OH protecting group that is removed in the deblocking step to allow for the next coupling reaction, but beginning in the 1990's, researchers developed large-scale parallel synthesis of DNA by replacing the DMTr group with a photolabile equivalent to allow for spatially selective deprotection. In particular, Affymetrix combined photolithographic techniques adapted from the semiconductor industry with the use of photolabile protecting groups for both peptide and DNA microarray synthesis . DNA microarray synthesis became the first ultra-large-scale genomics technology and contributed enormously to advances in genetics research. Even though the genomics applications of DNA microarrays have been partially eclipsed by advances in sequencing technologies, they remain widely used due to their low cost and accessibility. Nevertheless, new genomics applications specifically requiring DNA microarray technology are emerging, for example, array-based spatial transcriptomics, which makes use of spatially barcoded microarrays of reverse transcription primers to capture mRNA from tissue slices. As a chemical synthesis technology, however, microarrays remain a uniquely powerful tool for inexpensive and ultra-large-scale synthesis of oligonucleotides for either in situ use on the synthesis surface, or can be cleaved from the surface for off-array applications. Commercially, large-scale DNA arrays or array-derived DNA libraries are available from a variety of sources, including Affymetrix, Agilent, Illumina, CustomArray, and Twist Bioscience. Although the photolithographic approach pioneered by Affymetrix allows unmatched synthesis densities, two other spatially-selective synthetic approaches are relevant, particularly in the context of access to custom oligonucleotide libraries: ink-jet-based printing using activated DNA phosphoramidites instead of color inks , and an electrochemical approach using semiconductor chips containing arrays of individually addressable microelectrodes that generate a localized acidic environment for DMTr deblocking . Although the commercial availability of large DNA libraries is essential, their shortcomings include high cost and a restriction to the canonical DNA nucleotides. While DNA alone constitutes a very large and very useful combinatorial space, it is tiny and far less versatile than what is available from the much larger chemical space of natural and modified nucleosidic and non-nucleosidic building blocks that are relevant to many applications of nucleic acids, such as aptamers, nucleic acid therapeutics, and gene editing, which for the most part require RNA, and engineered or modified nucleic acid building blocks, often combined to enhance target binding, nuclease resistance or other desired therapeutic or analytical qualities .