Nanomaterials that respond to externally applied physical stimuli such as temperature, light, ultrasound, magnetic field and electric field have shown great potential for controlled and targeted delivery of therapeutic agents. However, the body of literature on programming these stimuli-responsive nanomaterials to attain the desired level of pharmacologic responses is still fragmented and has not been systematically reviewed. The purpose of this review is to summarize and synthesize the literature on various design strategies for simple and sophisticated programmable physical-stimuli-responsive nanotherapeutics.