Over the last 20 years, mesoporous silica nanoparticles (MSNs) have drawn considerable attention in the biomedical field due to their large surface area, porous network, biocompatibility, and abundant modification possibilities. MSN modification refers to the incorporation of materials such as alkoxysilanes, ions and nanoparticles (NPs) in the silica matrix during synthesis. Matrix modification is a popular approach for endowing MSNs with additional functionalities such as imaging properties, bioactivity, and degradability, while leaving the mesopores free for drug loading. As such, modified MSNs are considered promising theranostic agents. This review provides an extensive overview of different materials and modification strategies that have been used and their effect on MSN properties. We also highlight how modified MSNs have been applied in theranostic applications, oncology and regenerative medicine. We conclude with perspectives on the future outlooks and current challenges for the widespread clinical use of modified MSNs.