Diagnostic imaging techniques such as magnetic resonance imaging (MRI), ultrasound, and computerized tomography (CT) have had an enormous impact in clinical applications. Magnetic resonance imaging offers a noninvasive means to map brain structure and function by sampling the amount, flow, or environment of water protons in vivo. Intrinsic contrast can be augmented by the use of paramagnetic contrast agents in both clinical and experimental settings. However, these agents are little more than anatomical reporters which can at best label individual fluid compartments or distinguish tissues that are magnetically similar but histologically distinct. To permit a more direct imaging of the physiological state of cells or organs, an entirely new class of smart magnetic resonant imaging contrast agents has been developed that change their influence on the nearby water protons in a conditional fashion. The agents modulate fast water exchange, yielding distinct “on” and “off” states.