The pre-mature release of therapeutic cargos in the bloodstream or off-target sites is a major hurdle in drug delivery. However, stimuli-specific drug release responses are capable of providing greater control over the cargo release. Herein, various types of nanocarriers have been employed for such applications. Among various types of nanoparticles, mesoporous silica nanoparticles (MSNPs) have several attractive characteristics, such as high loading capacity, biocompatibility, small size, porous structure, high surface area, tunable pore size and ease of functionalization of the external and internal surfaces, which facilitates the entrapment and development of stimuli-dependent release of drugs. MSNPs could be modified with such stimuli-responsive entities like nucleic acid, peptides, polymers, organic molecules, etc., to prevent pre-mature cargo release, improving the therapeutic outcome. This controlled drug release system could be modulated to function upon extracellular or intracellular specific stimuli, including pH, enzyme, glucose, glutathione, light, temperature, etc., and thus provide minimal side effects at non-target sites. This system has great potential applications for the targeted delivery of therapeutics to treat clinically challenging diseases like cancer. This review summarizes the synthesis and design of stimuli-responsive release strategies of MSNP-based drug delivery systems along with investigations in biomedical applications.