The pharmacokinetic analysis of dynamic-contrast-enhanced (DCE) MRI data yields K trans and kep, two parameters independently measuring the capillary wall contrast reagent transfer rate. The almost universally used standard model (SM) embeds the implicit assumption that equilibrium transcytolemmal water exchange is effectively infinitely fast. In analyses of routine DCE-MRI data from 22 patients with suspicious breast lesions initially ruled positive by institutional screening protocols, the SM K trans values for benign and malignant lesions exhibit considerable overlap. A form of the shutter-speed model (SSM), which allows for finite exchange kinetics, agrees with the SM K trans value for each of the 15 benign lesions. However, it reveals that the SM underestimates K trans for each of the seven malignant tumors in this population. The fact that this phenomenon is unique to malignant tumors allows their complete discrimination from the benign lesions, as validated by comparison with gold-standard pathology analyses of subsequent biopsy tissue samples. Likewise, the SM overestimates k ep, particularly for the benign tumors. Thus, incorporation of the SSM into the screening protocols would have precluded all 68% of the biopsy/pathology procedures that yielded benign findings. The SM/SSM difference is well understood from molecular first principles.cancer ͉ water exchange ͉ MRI ͉ screening ͉ DCE S creening for breast cancer represents one of modern medicine's success stories. However, the continued large fraction of false positives in current diagnostic protocols (1) often leads to biopsy/ pathology procedures that append considerable pain, anxiety, healthcare cost, and possibly increased malignancy risk, but that are potentially avoidable. To address this problem, there have been recent calls for the increased use of magnetic resonance imaging (MRI) in breast screening (2, 3).Early in the development of medical MRI, it was realized that hydrophilic paramagnetic molecules could enhance image contrast, and that the shape of the water proton ( 1 H 2 O) signal intensity time course after a bolus injection of such a contrast reagent (CR) contained considerable patho-physiological information, promising even possible quantitative vascular phenotyping.Major efforts have been mounted for the pharmacokinetic analyses of such time-course data (4). It was natural that mathematical models for these were taken from the field of nuclear medicine, where such algorithms have matured. However, these were developed for tracer pharmacokinetics, with the intrinsic feature of direct radiotracer detection. Although the MRI CR plays the tracer role, the signal molecule remains water: the CR is detected only indirectly, via its effect on the nature of tissue 1 H 2 O relaxation. Affecting the recovery of longitudinal 1 H 2 O magnetization (i.e., in the magnetic field direction) requires (transient) water CR molecular interaction, as depicted in Fig. 1. The three major loci for tissue water, the cytoplasmae, the interstitium, and the bloo...