Pharmacogenetics of auto-immune diseases is a complex field of application for this relatively new discipline, since we still have a partial knowledge of the biological mechanisms of the disease and of the drugs currently used to treat it. We address a few key issues that emerge when planning a pharmacogenetic investigation in Multiple Sclerosis and that relate to the complexities existing at the biological-genetic level and at the phenotypic characterization. In fact, we think that a clearer characterization of the clinical phenotype representing the end-point of the investigation together with a critical appraisal of the multi-faceted dimension of the genetic component of either the disease and the pharmacogenetic profile of the drug investigated, will help to design more thorough study and to achieve deeper understanding of the practical results. We will primarily focus our research considerations on the role of Interferon Beta (IFN-beta) as a prototypal therapeutic agent in Multiple Sclerosis.