OBJECTIVES: The use of cost effectiveness analysis for treatments for rare diseases has proved difficult and alternative frameworks for assessing value and determining pricing and reimbursement have been sought. Here we summarise rare disease specific methodologies proposed in the literature. METHODS: A systematic literature review of Medline and EMBASE databases was conducted for the period 2000 – 2014 without geographic restriction. The search sought to identify papers that proposed specific frameworks for a) assessing the value of rare disease treatments or b) determining the price or reimbursement status of such drugs. Policy papers, commentaries, and review articles were included. Clinical or economic studies of specific rare diseases and their treatments were excluded.   RESULTS: The literature review identified 1,034 papers. Eleven studies proposed specific methods for assessing rare disease treatments. The most commonly proposed approach (7 of 11 papers) involved multi-criteria decision analysis. Of these studies, 5 proposed MCDA frameworks; one study applied and validated MCDA frameworks with rare disease stakeholders and another study investigated the relationship between MCDA domain attributes and the cost of rare disease drugs. Of non-MCDA methods, one study described a novel decision making framework that balances payer value factors with opportunity cost, and another discussed a policy framework for funding rare disease treatments in Ontario. Two studies specified non-value based pricing frameworks: one cost-based pricing and another ‘grant and access’ pricing. Limitations included challenges identifying representative societal preferences, determining the perspective from which value should be assessed, and resistance to transparency from decision makers. CONCLUSIONS: The need for a new framework for the evaluation of rare disease treatments has been commonly recognised in the published literature. A number of authors have proposed alternative approaches to cost effectiveness, but practical challenges are limiting their application currently.