Abstract: Polymer nanogels are nanosized crosslinked polymer networks, which have stable three-dimensional (3D) structures, high drug-loading efficiencies, stimuli-responsiveness, and so forth. The nanogels are part of the most promising nanoplatforms that find enormous applications in biomedicine fields such as drug delivery, gene therapy, and bioimaging. Compared with other polymer nanogels, polypeptide nanogels have gained wide attention in the biomedical areas due to excellent properties, such as great biocompatibility, fine stability, and nontoxicity of degradation products. Furthermore, the properties of polypeptide nanogels can be adjusted easily by alteration of side groups using ester exchange, "click", aminolysis, or other chemical reactions. There are two common routes for the preparation of polypeptide nanogels:(1) Crosslinking of the polypeptides prepared by polymerization of amino acid N-carboxyanhydrides (NCAs) with monofunctional NCA groups using cross-linking agents; (2) Polymerization of amino acid NCAs with difunctional NCA groups.On the basis of traditional polypeptide nanogels, other advantageous features can be added in order to improve the stability of the encapsulated drug and also achieve site-specific drug release. To this end, stimuli-responsive polypeptide nanogels have been developed which only release the payload at certain stimulating conditions, including endogenous stimuli (e.g., reduction, reactive oxygen species (ROS), pH, and enzymes) and exogenous stimuli (e.g., light and temperature). In this manner, the drug molecules can remain stable in the nanocarrier during circulation until arriving at the target area, where drugs are released with appropriate physical or chemical transitions of polypeptide nanogels, e.g., shrinking, swelling, or disintegration. As controlled drug release continues to be a desired characteristic of a drug delivery system, functional polypeptide nanogels play an important role in the advances of nanomedicines. In this feature article, a comprehensive introduction of the preparation and applications of diverse stimuli-responsive polypeptide nanogels are illustrated. The challenges regarding polypeptide nanogels applications are given and potential opportunities in addressing them are also predicted.