Access to very large chemical libraries opens new opportunities in drug discovery but presents major scalability challenges for traditional chemical screening workflows. Commercial libraries, which are the primary source of compounds in academic screening efforts, can be grouped into two categories: "in-stock" and "synthesize-on-demand." As of 2021, in-stock libraries comprise over 12 million molecules previously synthesized and physically stored by vendors. Synthesize-on-demand libraries are databases containing virtual molecules that a vendor considers to be readily accessible given stocks of available building blocks and established synthetic routes. Such libraries now measure in the billions: the ZINC-22 database aggregates 37 billion compounds from the Enamine REAL, WuXi GalaXi, and Mcule Ultimate catalogs. Synthesize-on-demand libraries have superior chemical scaffold diversity and coverage of chemical shape characteristics, unlocking new possibilities to manipulate biological targets. The growth of synthesize-on-demand libraries has been disruptive, requiring new scalable strategies for enumerating, storing, and searching them. However, the question remains as to how to effectively prioritize molecules from synthesize-on-demand libraries for acquisition and testing in the hit identification phase of drug discovery projects.