Most drugs are toxic to cells that often kill healthy cells and establish several side effects. Conventional chemotherapy cargoes are not tumor-specific and commonly their nature leads to significant toxic effects on healthy tissues. Therefore, several drug delivery systems (DDSs) were developed to amend the therapeutic properties of drugs and made them safer and more effective. Local drug delivery which decreases systemic drug exposure, is an important approach for maximal efficacy, high levels of patient compliance, and fewer side effects. Smart drug delivery systems (SDDSs) have gained much attention and paved the way for more effective treatment of patients. SDDSs with stimuli-responsive characteristics are determined as the process that the payloads are not released before reaching the target site. This triggered release occurs due to the variations in the nano/microcarrier chemistry and structure, in response to endogenous and/or exogenous stimulus, establishing the release of the cargoes to the exact place. Responsive and smart materials/biomaterials are responsive/sensitive to signals originating from physiological systems, or to abnormalities originating from pathological defects, that can interact with or be triggered by the biological environments, and are interesting in drug delivery platforms/devices for developing next-generation accurate medicines. In exogenous-triggered delivery, drug/gene release is controlled by external stimulus, which can be controlled exactly. Different exogenous triggers have been reported, such as light, magnetic field, temperature, electrical field, and ultrasound. The endogenous triggers such as pH, redox, enzyme concentration, and bio-molecules are related to the disease's pathological characteristics. Disease pathological characteristics are key parameters as physiological triggers for designing programmed delivery devices that may be used for the non-invasive and effective treatment of a wide range of pathological conditions such as cancer, infections, diabetes, cardiovascular diseases, autoimmune disorders, stroke, and chronic wounds, and degenerative diseases. Endogenously triggered drug release is the same as exogenously triggered drug release, which can lead to enhanced release of therapeutic molecules at the target place in its therapeutic concentration, reducing local toxicity and side effects, reducing the need for repeat administrations, and increasing patient compliance. Here, we focused on smart endogenous and exogenous stimuli-responsive biomaterials for programmed drug delivery. The conventional drug delivery systems are not without any limitations and challenges. One of the most important challenges is related to their degradability or insufficient biocompatibility of most materials which are used in smart delivery system. Another challenge is related to the using of 2D in vitro models or in vivo animal studies to evaluate the performance of these systems, and there is a poor relation between such results and human clinical trials. Thus, these incompatibilities can lead to the failing of the numerous smart systems in clinical studies. In this special issue, we focus on smart multi-responsive drug delivery systems that can address some challenges and drawbacks. Research paper, commutation (letter), mini-review and review are acceptable for publications in this special issue. Main topics: 1- Smart exogenous-triggered delivery systems 2- Smart endogenous-triggered delivery systems 3- Multi-responsive targeted vehicles 4- Stimuli-responsive niosomes and liposomes 5- Multifunctional biomaterials for cancer treatment 6- Smart 3D and 4D scaffolds for localized delivery systems