Spontaneous remyelination occurs in multiple sclerosis (MS) patients. However, this process is not robust enough to promote a functional and stable recovery of the myelin architecture in demyelinated areas of the central nervous system (CNS). As a consequence of this incomplete reparative process, the disease invariably progresses and patchy areas of demyelination-in which axonal damage and/or loss is a constant accompanying factor-increase over time and lead to the accumulation of irreversible neurological deficits. Thus, the development of cell-based therapies aimed to promote multifocal remyelination in MS represents one of the most challenging areas of investigation. Several cell-replacement strategies have been developed in the last few years. However, most of these therapeutic approaches-although consistently able to form new myelin sheaths around the transplantation site-are unrealistic owing to the multifocality of the demyelinating process and the inability to in vitro growth and differentiate large number of myelin-forming cells. Recently, promising cell-replacement therapies based on the use of stem cells have been proposed. However, before envisaging any potential human applications of such therapies we need to confront with some preliminary and still unsolved questions: (i) the ideal stem cell source for transplantation, (ii) the route of cell administration, (iii) the differentiation and persistence of stem cells into the targeted tissue and, last but not least, (iv) the functional and long-lasting integration of transplanted cells into the host tissue.