The medical profession's modern quandaries with Multiple Sclerosis (MS) largely began in 1849, with Friedrich von Frerichs' (1819–1885) early description of the clinical and pathological features of what he termed Hirnsklerose (“brain sclerosis”). This manuscript is an overview of the century of research (1850–1950) that followed the emergence of this clinical entity, with a focus on the hitherto under-explored English Canadian perspective. Using journal articles, reviews, and case studies, this historiographical paper reviews what may be some of the earliest recorded cases of MS in Canada, and outlines the diagnostic challenges that confronted early Canadian physicians in their encounters with MS. Early Canadian attempts to characterize the aetiology and epidemiology of MS and treat it are also discussed. These activities were influenced by developments in the field in Europe and the United States, and helped set the stage for the modern era of immunologic and therapeutic research on MS.