Book excerpt: Stimuli-responsive polymers have already showed tremendous promise in controlled and self-regulated drug delivery. Successful construction of responsive polymers requires amalgamation of chemical, physical and biological principles. For careful therapy, a great deal of advantages offered by stimuli-responsive polymers is essential. A small or modest change in the environmental condition (e.g. temperature, pH, light) brings a sharp change in the properties of the responsive polymers. `Smart' drug delivery systems utilize these principles to mimic the biological response behavior to a certain extent. Synthetic polymers incorporated with stimuli-responsive behavior would be amenable to overcome some of the systemic and intracellular delivery barriers. Development in material science has led to the engineering of variety of smart polymers which respond to diverse biological stimuli. The current research illustrates the development of two dual-stimuli-responsive polymers applied for local drug delivery. The polymers form thermogels at body temperature and degrade in either acidic or matrix metalloproteinase rich environments. The polymers were synthesized from Pluronic® tri-block copolymers in two simple reaction schemes and thoroughly characterized for structures, physicochemical properties and cytotoxicity. The underlying principles involved in physicochemical behavior of polymers and polymer solutions were clearly discussed. The release characteristics of different therapeutic agents such as small molecule drugs, genes and proteins from the thermogels were investigated. Finally, to improve the release properties of small size proteins, a nanocomposite thermogel system was developed. The nanocomposite thermogel was based on a nanoclay, laponite, and pH-sensitive thermogelling polymer. Finally, the nanocomposite thermogel incorporated with laponite sustained the release properties of small proteins comparing to regular thermogels. Taken all together, the novel thermosensitive polymers and nanocomposite thermogel system have great potential for bioresponsive local drug delivery where the amount of bioactive release entirely depends on physiological needs.