This review focuses on MR contrast agents that are responsive to a change in physiological environment. The "response" mechanisms are dependent on 6 physicochemical phenomena, including the accessibility of water to the agent, rotational tumbling time, proton exchange rate, electron spin state, MR frequency, or local field inhomogenieties caused by the agent. These phenomena can be affected by the physiological environment, including changes in concentrations or activities of proteins, enzymes, nucleic acids, metabolites, oxygen and metal ions, and changes in pH and temperature. A total of 52 examples are presented, which demonstrate the variety and creativity of different approaches used to create responsive MRI contrast agents.