Purpose <p>4D printing of hydrogels has emerged as a promising approach for developing advanced drug delivery systems. By incorporating stimuli-responsive materials and time-dependent shape transformations, 4D-printed hydrogels offer unprecedented control over the spatial and temporal release of therapeutic agents. This review aims to provide a comprehensive overview of the fundamental principles, materials, and strategies employed in 4D printing of hydrogels for drug delivery applications.</p> Methods <p>A thorough review of the literature was conducted using databases such as PubMed, Scopus, and Google Scholar, focusing on keywords including “4D printing,” “hydrogels,” “stimuli-responsive drug delivery,” and “advanced therapeutic systems.” English-language studies emphasizing the mechanisms of shape transformation, stimuli-responsive hydrogels, printing strategies, and biomedical applications were included.</p> Results <p>The review highlights the distinction betwe en 3D and 4D printing, emphasizing the mechanisms underlying shape transformations and the utilization of stimuli-responsive hydrogels. Various responsive systems such as temperature-, pH-, enzyme-, light-, magnetic-, and electric field-responsive hydrogels, along with multi-stimuli responsive materials, are discussed. Strategies tailored for drug delivery are detailed, including time-programed release architectures, on-demand and triggered release systems, multi-compartment and core-shell constructs, and integrated control through modeling and design. The integration of 4D printing with bioprinting and tissue engineering is addressed, focusing on co-printing of cells for tissue-drug hybrid constructs, applications in organ-on-chip and wound healing models, and personalized medicine through patient-specific drug release scaffolds. Challenges related to material limitations, shape programming complexity, biological and clinical factors, as well as emerging trends such as nanotechnology integration, bioelectronics, and wireless control systems are also explored.</p> Conclusions <p>This review discusses the advances, challenges, and future outlook of 4D-printed hydrogels for drug delivery. With ongoing innovations in stimuli-responsive materials, advanced printing strategies, and integration with biotechnologies, 4D printing holds significant potential to revolutionize drug delivery by offering precise, adaptive, and personalized therapeutic platforms that ultimately enhance patient health and well-being.</p> Lay Summary <p> 4D printing of hydrogels represents an advanced approach for drug delivery, allowing for dynamic and time-dependent release of therapeutic agents. These smart systems respond to environmental cues like temperature, pH, or light to control when and where drugs are delivered, improving treatment efficiency and overall well-being. By integrating cells and designing patient-specific scaffolds, 4D-printed hydrogels pave the way for personalized medicine and advanced healing solutions. Despite challenges such as material constraints and biological compatibility, these technologies are shaping the future of controlled, responsive drug therapies.</p>