In order to address the shortcomings of traditional therapeutic modalities, this study offers a thorough review of stimuli-responsive drug delivery systems (DDS) for programmed site-specific release that are based on both endogenous and exogenous stimuli. This work focuses on the smart materials and mechanism of action of several stimuli-responsive polymeric carriers, which are important in both the extracellular and intracellular domains of diseased tissues or cells. Research is being conducted globally to design new stimuli-responsive carriers, both internal and external, for biotechnological applications in general and biomedical and/or pharmaceutical applications in particular. This is because science has an ever-expanding body of knowledge and awareness. An essential component of designing so-called smart DDS, which sophisticatedly regulates dose loading, sustained release, individual variability, and targeted permeability, is the carriers’ dual-/multi-responsive, internal, and even external behaviors. Various stimulus-responsive DDS have been developed, proposed, and utilized thus far. These include systems responsive to electrical, magnetic, pH, temperature, photo/light-induced reactions, and redox stimuli. Additionally, dual and multi-responsive DDS, which combine two or more of these stimuli, have been explored for enhanced therapeutic efficiency. In order to close the research gap, a number of difficult issues still need to be resolved despite the tremendous advancements made in the DDS field. To fill in the gaps in the literature, an attempt has been made to draw attention to those important issues in this context. As a result, the focus was on the mechanisms of drug release and the clinical applications of exogenous and endogenous stimuli-responsive DDS.