Because of the availability of large compound collections on the Web, elementary cheminformatics tasks such as chemical library browsing, analyzing, filtering, or unifying have become widespread in the life science community. Furthermore, the high performance of desktop hardware allows an interactive, problem-driven approach to these tasks, avoiding rigid processing scripts and workflows. Here, we present MONA 2, which is the second major release of our cheminformatics desktop application addressing this need. Using MONA requires neither complex database setups nor expert knowledge of cheminformatics. A new molecular set concept purely based on structural entities rather than individual compounds has allowed the development of an intuitive user interface. Based on a chemically precise, high-performance software library, typical tasks on chemical libraries with up to one million compounds can be performed mostly interactively. This paper describes the functionality of MONA, its fundamental concepts, and a collection of application scenarios ranging from file conversion, compound library curation, and management to the post-processing of large-scale experiments.