Water desalination via reverse osmosis (RO) to produce fresh water represents an ideal solution to address water shortage. Membranes of large water permeability and high salt rejection are desired, and these properties are subject to the design of the membrane structure. The structural tunability of metal-organic frameworks (MOFs) therefore provide tremendous opportunities, but their potential has not yet been systematically explored. In this study, molecular dynamics simulations are conducted to investigate MOFs with a focus on a subclass of water stable Zirconium-based MOFs as RO membranes in water desalination. The results show that MOF membranes can indeed achieve a perfect salt rejection while allowing notably high permeability as compared to commercial polymeric membranes. Moreover, the structure-performance relationship is explored, and the critical role of channel homogeneity is identified. Overall, the outcomes of this study demonstrate the great promise of MOFs and provide guidelines on the selection and design of MOFs for effective and efficient water desalination.