The use of self-assembled monolayers (SAMs) for the functionalization of surfaces is extremely widespread among the scientific community, because they are easy to prepare and thermodynamically stable. Inferior binding uniformity, packing density, and molecular alignment have recently been observed also for SAMs made of thioether-based tripodal ligands with respect to the corresponding SAMs made of thiol-based tripodal ligands. This chapter presents an overview of the literature on smart mono-layers which respond to different stimuli both for their characterization and for their interaction with other molecules. It talks about mono-layers such as light-responsive, temperature-responsive, ph-responsive, electrochemically responsive and multi-responsive monolayers in detail. The examples described in the chapter show the high importance of smart SAMs for surface characterization, postimmobilization monitoring, and switching processes.