Drug affinity responsive target stability (DARTS) is a method of drug target ID with several significant advantages over current techniques. In certain embodiments the method involves contacting a sample comprising one or more protein target(s) with a test agent to form a sample/test agent mixture; contacting the mixture with a protease; and identifying a protein or protein fragment that is protected from proteolysis, wherein the protection from proteolysis is an indicator that the protein or protein fragment binds to or interacts with the test agent.