According to the World Health Organization, cancer accounted for 19.9 million incidences globally, in 2022, while 48.7% (9.7 million) of these cases resulted in deaths. These staggering statistics demand an immediate need for effective anti-cancer therapies. The current therapeutic options for cancer include surgery, chemotherapy, radiotherapy, and immunotherapy either alone or in combination. However, these therapies result in off-target interactions causing severe side effects. To circumvent this drawback, nanoparticles are used as a drug delivery system. Mesoporous silica nanoparticles (MSNs) are one of the classes of nanoparticles, commonly under investigation as an anti-cancer drug delivery system. MSNs offer a multitude of advantages, such as a uniform porous structure and a high surface area for improved drug loading, good biocompatibility, and ease of surface functionalization. To achieve spatio-temporal control over the release of anticancer therapeutics, MSNs are modified with stimuli-responsive moieties. As a result, these “smart” MSNs have garnered interest in the field of precision medicine. This chapter highlights the recent advancements of stimuli-responsive MSNs encompassing both endogenous and exogenous stimuli for cancer therapy. Strategies employed in the design of MSNs responsive to endogenous stimuli (such as pH, redox, and enzyme), and exogenous stimuli (such as light, heat, ultrasound, and magnetic field) are addressed. The chapter further discusses the strategies to develop hybrid-stimuli-responsive MSNs for cancer therapy. Moreover, their pre-clinical studies and clinical status have been summarized. Finally, the challenges and future perspective of stimuli-responsive MSNs have also been outlined.