Controlled drug delivery systems, which could release loaded therapeutics upon physicochemical changes imposed by physiological triggers in the desired zone and during the required period of time, offer numerous advantages over traditional drug carriers including enhanced therapeutic effects and reduced toxicity. A polypeptide is a biocompatible and biodegradable polymer, which can be conveniently endowed with stimuli-responsiveness by introducing natural amino acid residues with innate stimuli-responsive characteristics or introducing responsive moieties to its side chains using simple conjugating methods, rendering it an ideal biomedical material for controlled drug delivery. This feature article summarizes our recent work and other relevant studies on the development of polypeptide-based drug delivery systems that respond to single or multiple physiological stimuli (e.g., pH, redox potential, glucose, and hypoxia) for controlled drug delivery applications. The material designs, synthetic strategies, loading and controlled-release mechanisms of drugs, and biomedical applications of these stimuli-responsive polypeptides-based drug delivery systems are elaborated. Finally, the challenges and opportunities in this field are briefly discussed.