Here, we discuss the physicochemical properties of both bulk and nanosheets of III–VI and IV–VI metal chalcogenides and their application capabilities in electrocatalysis, photocatalysis, and gas sensing by combining density function theory with surface‐science experiments. In particular, GaSe, InSe, and GeSe are van der Waals semiconductors stable in water media and robust against CO poisoning, which make them suitable candidates for application as low‐cost (photo)catalysts in liquid media. Both bulk and exfoliated III–VI and IV–VI metal chalcogenides are prone to oxidation, with the formation of an oxide skin in oxidative environments. The self‐assembled heterostructure formed by the oxide skin and the underlying bulk of metal chalcogenides makes the Heyrovsky step of HER energetically favourable. Both metal and Se vacancies are necessary to decrease the energy barrier for HER in acid media. The …