The phenomenon known as Leao’s spreading depression is investigated in this collection of ten original articles. New ideas about the fundamental mechanisms, which focus on the involvement of polyunsaturated fatty acids and free radicals, are presented. The relationship of spreading depression with clinical entities such as migraine, epilepsy, ischemic and protein-deficiency conditions of the nervous tissue are discussed as well. Studies dealing with the application of non-invasive techniques to monitor the disease are included.