EPR can uniquely measure paramagnetic species. Although commercial EPR was introduced in 1950s, the early studies were mostly restricted to chemicals in solution or cellular experiments using X-band EPR equipment. Due to its limited penetration (<1 mm), experiments with living animals were almost impossible. To overcome these difficulties, Swartz group, along with several other leaders in field, pioneered the technology of low frequency EPR (e.g., L-band, 1-2 GHz). The development of low frequency EPR and the associated probes have dramatically expanded the application of EPR technology into the biomedical research field, providing answers to important scientific questions by measuring specific parameters that are impossible or very difficult to obtain by other approaches. In this review, which is aimed at highlighting the seminal contribution from Swartz group over the last several decades, we will focus on the development of EPR technology that was designed to deal with the potential challenges arising from conducting EPR spectroscopy in living animals. The second half of the review will be concentrated on the application of low frequency EPR in measuring cerebral tissue pO 2 changes and oxidative stress in various physiological and pathophysiological conditions in the brain of animal disease models.