This historical review describes the evolution of pathogenetic concepts of multiple sclerosis (MS) from the viewpoint of pathology. MS research is based on studies of descriptive neuropathology, performed during the 19th and early-20th century, which defined the basic nature of the inflammatory demyelinating lesions. Advances in basic immunology and neurobiology, performed during the second half of the 20th century, paved the way for the understanding of the molecular mechanims involved in inflammation and well as tissue destruction in this disease. However, recent clinical and neuroradiological studies on the evolution of the disease and its brain lesions as well as ongoing attempts to define the genetic basis of the disease indicate that our current pathogenetic concepts may be too simple and that essential aspects of MS pathology have to be redefined.