The human body is a complex system where several interconnected dynamic processes work in an orchestrated manner to carry out the many different body functions. However, pathological conditions may cause dysregulations of these body functions. Biomedicine aims to understand such dysregulations and restore normal, healthy function within bodies. A wide variety of therapeutics have been used since ancient times, but their traditional systemic administration lacks spatiotemporal control over the delivery. Recent progress in chemistry and physics, along with the emergence of nanotechnology, has allowed the development of new strategies to solve this drawback such as stimuli-responsive nanobiomaterials. This new class of materials can be designed to respond to chemical and physical stimuli associated with pathological dysregulations (for example, changes in pH or redox environment, or the increase of certain biomolecules in the bloodstream). Alternatively, stimuli can also be provided externally (such as magnetic fields or light) to trigger the controlled release of therapeutics. Hydrogels are one of the most promising materials to achieve complete spatiotemporal control as they are typically injected or implanted where they are needed. Moreover, the chemical structure of the polymers forming the hydrogel can be easily manipulated to make them stimuli-responsive. This chapter focuses on the chemical and physical mechanisms that confer stimuli-responsive properties to polymers, enabling the development of smart hydrogels for spatiotemporal delivery of drugs.