Chemical-stimuli-responsive nanotherapeutics have gained great interest in drug delivery and diagnosis applications. These nanotherapeutics are designed to respond to specific internal stimuli including pH, ionic strength, redox, reactive oxygen species, glucose, enzymes, ATP and hypoxia for site-specific and responsive or triggered release of payloads and/or biomarker detections. This review systematically and comprehensively addresses up-to-date technological and design strategies, and challenges nanomaterials to be used for triggered release and sensing in response to chemical stimuli.