Polymeric nanoparticles are promising candidates as drug and gene carriers. Among polymeric nanoparticles, those that are responsive to internal or external stimuli are of greater interest because they allow more efficient delivery of therapeutics to pathological regions. Stimulus-sensitive polymeric nanoparticles have been fabricated based on numerous nanostructures, including micelles, vesicles, crosslinked nanoparticles, and hybrid nanoparticles. The changes in chemical or physical properties of polymeric nanoparticles that occur in response to single, dual, or multiple stimuli endow these nanoparticles with the ability to retain cargoes during circulation, target the pathological region, and release their cargoes after cell internalization. This Review focuses on the most recent developments in the preparation of stimulus-sensitive polymeric nanoparticles and their applications in drug and gene delivery.