This review provides an overview of the current state of the art of magnetic resonance spectroscopy (MRS) in in vivo investigations of diffuse liver disease. So far, MRS of the human liver in vivo has mainly been used as a research tool rather than a clinical tool. The liver is particularly suitable for static and dynamic metabolic studies due to its high metabolic activity. Furthermore, its relatively superficial position allows excellent MRS localization, while its large volume allows detection of signals with relatively low intensity. This review describes the application of MRS to study the metabolic consequences of different conditions including diffuse and chronic liver diseases, congenital diseases, diabetes, and the presence of a distant malignancy on hepatic metabolism. In addition, future prospects of MRS are discussed. It is anticipated that future technical developments such as clinical MRS magnets with higher field strength (3 T) and improved delineation of multi-component signals such as phosphomonoester and phosphodiester using proton decoupling, especially if combined with price reductions for stable isotope tracers, will lead to intensified research into metabolic syndrome, cardiovascular disease, hepato-biliary diseases, as well as non-metastatic liver metabolism in patients with a distant malignant tumor.