Energy failure is an emerging concept in multiple sclerosis research. Pathological studies have indicated that axonal modifications in response to demyelination may increase neuronal energy demand. At the same time, soluble mediators of inflammation may impair mitochondrial function, and brain perfusion may also be decreased. Insufficient energy production for demand can lead to intracellular sodium accumulation, calcium influx and cell death. Magnetic resonance (MR) is a promising technique to investigate these pathology driven hypotheses in vivo. MR spectroscopy can inform on mitochondrial function with measures of N acetyl aspartate (NAA), and requirement for extra-mitochondrial glycolysis via measurement of lactate. MR measurement of phosphorous ((31)P) and sodium ((23)Na) allows direct assessment of energy availability and axonal sodium handling. MR techniques for imaging perfusion can quantify oxygen delivery and nascent MR techniques that exploit the paramagnetism of deoxyhaemaglobin may be able to quantify oxygen utilization. This report reviews the physical principles underlying these techniques, their implementation for human in vivo imaging, and their application in neurological conditions with an emphasis on multiple sclerosis. Combination of these techniques to obtain a comprehensive picture of oxygen delivery, energy production and utilization may provide new insights into the pathophysiology of multiple sclerosis and may provide outcome measures for trials of novel treatments.