Since metal oxide surfaces are chemically stable in aqueous solutions, their atomic structures and chemical properties can be utilized in nanofabrication and nano-biotechnology in aqueous environment. This article describes phenomena related to water layers on single-crystalline metal oxide surfaces. On sapphire (0001) surfaces, domain structures with different hydrophilicity and charged states are spontaneously formed during thermal annealing. This surface exhibits domain-selective adsorption of protein molecules. Phase separation on metal oxide surfaces is classified into structural and chemical ones. On the chemically phase-separated surfaces, terraces with different surface chemistry coexist. Surface chemistry in aqueous environment can be characterized by adsorption force measurement of a tip to the substrate surface using atomic force microscopy (AFM). Water layers on a metal oxide surface can be observed by AFM by attaching graphene films to the oxide surface. Chemical phase separation on titania (100) surfaces is also demonstrated.