Mesoporous silica, which shows well-defined pore systems, tunable pore diameters (2–30 nm), narrow pore size distributions and high surface areas (>600 m² g⁻¹), is frequently modified using different methodologies (including in situ and post-synthetic strategies) to introduce various chemical functionalities useful in applications like catalysis, separation, drug delivery, and sensing. This contribution aims to provide a critical overview of the various strategies to incorporate chemical functionalities in mesoporous silica highlighting the advantages of the in situ methods based on the bottom-up construction of mesoporous silica containing various chemical functionalities in its structure.