Proton-coupled electron transfer (PCET) plays an important role in many chemical processes, both in living matter as well as in technologically relevant molecular systems. It often involves energetically coupled transitions of several electrons and protons. The richness of PCET reaction mechanisms severely complicates the analysis and interpretation of experimental observations and calls for guidance and support of computational methods. Theoretical approaches of quantum chemistry could provide a very accurate description of PCET events, but face a number of methodological and practical limitations. In this chapter, the main challenges of describing PCET events in large biomolecular systems with quantum chemical methods are considered. The advantages and limitations of various approaches are critically discussed and the author’s view on a potential future route to realistic large-scale PCET simulations is provided. It is concluded that a new cost-efficient theoretical approach based on the ideas of Frozen-Density Embedding and the Nuclear Electronic Orbital technique could be a promising avenue.