Stimuli-responsive "smart" hydrogel biomaterials have attracted great attention in the biomedical field, especially in designing novel on-demand drug delivery systems. As a handful natural biomaterial approved by US Food and Drug Administration, silk fibroin (SF) has unique high temperature resistance as well as tunable structural composition. These properties make it one of the most ideal candidates for on-demand drug delivery. Meanwhile, recent advances in polymer modification and nanomaterials have fostered the development of various stimuli-responsive delivery systems. Here, we first review the recent advance in designing responsive SF-based delivery systems in different stimulus sources. These systems are able to release mediators in a desired manner in response to specific stimuli in active or passive manners. We then describe applications of these specially designed responsive delivery systems in wound healing, tumor therapy, as well as immunomodulation. We also discuss the future challenges and prospects of stimuli-responsive SF-based delivery systems.