Combinatorial variant libraries accelerate exploration of the large variant space in antibody engineering, pathway engineering, and protein engineering. Traditional library fabrication methods, such as NNK and Trimers, can introduce premature stop codons or redundant codons, leading to poor control over diversity and an uneven amino acid distribution. Twist Bioscience’s silicon-based DNA synthesis platform, on the other hand, enables precise synthesis of high-diversity domain libraries at user-defined ratios and without the incorporation of unwanted motifs. We highlight Twist Bioscience’s ability to construct complex, highdiversity libraries at confined regions (for example, CDRs) and introduce technology advancements that enable construction of synthetic DNA libraries with diversity scattered along the length of constructs. We demonstrate the precision of this technology through next-generation DNA sequencing validation. This technology provides a powerful solution for focusing libraries to precisely interrogate the variant space and enables users to make iterative designs that hone in on the target.