A legislative framework introducing European public health measures on orphan medicinal products came into force in the European Union in April 2000. The aim of the orphan legislation is to stimulate research and development of medicinal products for rare diseases by providing incentives to the sponsors. Incentives include, among others, an unreserved access to the centralized procedure with a 10-year period of market exclusivity and fee reductions including free scientific advice for drug development. Nine years after the implementation of the orphan legislation, more than 690 products have been designated and 58 have received marketing authorizations in Europe. The orphan designations granted to date cover a wide variety of diseases for which there are either no authorized treatments or only limited treatment options with a need for improvement. At the dawn of the tenth anniversary of the orphan legislation, the aim of this article is to review how the European Medicines Agency has supported the mechanisms fostering development of orphan medicines in the E.U. since 2000.