In this context, health systems have taken into account other factors in the funding of medicines beyond the cost of production. Economic evaluation has been given a leading role as a tool to distribute available resources in the most efficient and fair way possible. The funding of orphan drugs involves different challenges for healthcare systems. The way in which regulators undertake the funding of pharmaceutical therapies aimed at rare diseases will be a crucial factor to create incentives for investment in R&D and will be determinant to achieve greater access to medicines by patients, as well as ensuring the sustainability of public health systems. It is in this triad of challenges, where the economic evaluation of medicines for rare diseases, which allow the prioritization of resources, can not give an adequate response. Therefore, a consensus is needed on how regulators should try to pay for these drugs, in relation to the value they bring to the health system and the society.