One of the hallmarks of cancer is the unlimited potential for cell replication , which leads to changes in tissue microstructure, such as increased cellularity and decreased extracellular volume fraction (ECVF), compared with healthy tissue. Successful treatment with radiation therapy and chemotherapy results in increased ECVF, decreased cellularity, and a loss of cell membrane integrity [2-4]. šese changes can be detected indirectly with di›usion-weighted magnetic resonance imaging (DW-MRI), which provides information about tissue microstructure by means of a noninvasive magnetic resonance (MR) imaging sequence that is sensitive to the motion of water molecules. In this chapter, the biological basis for changes observed with DW-MRI and the imaging mechanism behind the technique will be described, along with practical considerations. Evidence for its potential as a valuable imaging biomarker (Biomarkers Deœnitions Working Group 2001) for the detection, staging, and monitoring of therapy in cancer will be presented, and, œnally, future directions for the technique will be discussed.