Ac omprehensive model to describe the water stability of prototypical metal-organic frameworks (MOFs) is derivedby combining different types of theoretical and experimental approaches. The resultsp rovide an insight into the early stages of water-triggered destabilization of MOFs and allow detailed pathways to be proposed for the degradation of different MOFs under aqueous conditions. The essential elements of the approach are computing the pK a values of coordinated water molecules and geometry relaxations. Variable-temperature and pH infrared spectroscopy techniques are used to corroborate the main findings. The model developed herein helpst oe xplain stabilityl imits ob-servedf or severalp rototypical MOFs, including MOF-5, HKUST-1, UiO-66, and MIL-101-Cr,i na queouss olutions,a nd thus, providesa ni nsighti nto the possible degradation pathways in acidic and basic environments. The formation of a metalh ydroxide through the autoprotolysis of metal-coordinated water molecules and the strength of carboxylatemetali nteractions are suggested to be two key players that govern stability in basic and acidic media, respectively.T he methodology presentedh erein can effectivelyg uide future efforts, which are especially significantf or in silico screening, for developing novel MOFs with enhanced aqueous stability.[a] M.Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.