Diffusion-weighted magnetic resonance imaging (DWI) provides information on the diffusivity of water molecules in the human body. Technological advances and the development of the concept of diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) have opened the path for routine clinical whole-body DWI. Whole-body DWI allows detection and characterization of both oncological and non-oncological lesions throughout the entire body. This article reviews the basic principles of DWI and the development of whole-body DWI, illustrates its potential clinical applications, and discusses its limitations and challenges.