We wanted to revise the widely used ZINC platform to address key problems that medicinal chemists, structural biologists and chemical biologists will inevitably encounter to engage with this growing tangible space. First, we wanted to address the apparently simple problem of seeking analogs for a particular compound or series of compounds. This was trivially done for libraries of several million molecules but collapses as one approaches a billion molecules. A method to do this was described in a previous study, here we focus on the development of a facile and integrated GUI, CartBlanche, to facilitate these searches and organize the results. Second, we continue to support molecular structure and property calculation for physical modeling, often molecular docking-an initial motivation for the database . As we move into the multi-billion molecule space, the organization of the data in ZINC has had to change. In building ZINC-22, we investigated data organization schemes that address challenges in disk access, rapid lookup, database distribution and download, and the relational structure of the database. Third, and perhaps most interesting from a chemical space and chemical information standpoint, we consider how the growth of the libraries has changed the properties of the molecules represented, their diversity, and what the limits to growth of a library like ZINC might be. Finally, as daunting and as exciting as our new world of 10 to 100 billion molecules is, it remains a tiny fraction of drug-like chemical space. How we might expect to engage with multi-trillions of molecules will also be considered.