Mn-JED is a new biochemically responsive MRI contrast agent that provides 9-fold relaxivity change by switching between the Mn(3+) and Mn(2+) oxidation states. The JED chelator is the only chelator that supports both the Mn(3+) and Mn(2+) oxidation states in biological milieu. Rapid interconversion between oxidation states is achieved by peroxidase activity (oxidation) and cysteine (reduction). Peroxidase activity is drastically elevated during acute inflammation. Thiols such as cysteine are overabundant in the microenvironment of proliferative tumors. Mn-JED provides a new paradigm for the design of biochemically responsive MRI contrast agents.