H imaging is concerned with contrast generation among anatomically distinct soft tissues. X-nuclei imaging, on the other hand, aims to reveal the underlying changes in the physiological processes on a cellular level. Advanced clinical MR hardware systems improved H image quality and simultaneously enabled X-nuclei imaging. Adaptation of H methods and optimization of both sequence design and postprocessing protocols launched X-nuclei imaging past feasibility studies and into clinical studies. This review outlines the current state of X-nuclei MRI, with the focus on Na, Cl, K, and O. Currently, various aspects of technical challenges limit the possibilities of clinical X-nuclei MRI applications. To address these challenges, quintessential physical and technical concepts behind different applications are presented, and the advantages and drawbacks are delineated. The working process for methods such as quantification and multiquantum imaging is shown step-by-step. Clinical examples are provided to underline the potential value of X-nuclei imaging in multifaceted areas of application. In conclusion, the scope of the latest technical advance is outlined, and suggestions to overcome the most fundamental hurdles on the way into clinical routine by leveraging the full potential of X-nuclei imaging are presented. Level of Evidence: 1 Technical Efficacy Stage: 3 J. Magn. Reson. Imaging 2019.