The functionalization of mesoporous silica nanoparticles (MSNs) is a very important step in the preparation of these systems for a variety of applications. The surface of MSNs can be widely functionalized with different organic groups. There are essentially two ways to covalently modify the surface of nanoparticles: co-condensation and post-grafting. Generally, for both of these methods, the precursors are: [(R'O)3SiR] and [Cl3SiR]. The paper summarizes the main experimental contributions and the recent advances in the study of interactions among organosilanes and the MSNs surface. In particular, it provides relevant and innovative examples of Solid State and Solution NMR (SSNMR and SolNMR) and Fourier Transform InfraRed (FTIR) spectroscopy that highlight different possible approaches to understand the MSNs-pendants interaction.