OBJECTIVES: In 1983 the US Orphan Drug Act (ODA) was passed to facilitate commercialization of drugs to treat rare diseases. The market value for orphan drugs in the US reached $90 billion annually in 2014, with worldwide sales forecast at $176 billion. Payers and policymakers need robust methodology for evaluation of health technology in this growing landscape of expensive treatments for rare diseases. Here we present a systematic review of current practices in value-based evaluation of orphan drugs from a global perspective. METHODS: Searches were conducted in December 2015 in MEDLINE®, EMBASE®, and Web of Science® databases using the following keywords: orphan drug, rare disease treatment, economics, resource utilization, cost, cost effectiveness, questionnaire, and value. Only references published in English were included. Manuscripts that solely reported one of the following were excluded: clinical or patient care, policy or legislation on orphan drugs particularly relating to research incentive, opinion or editorial, preclinical studies, drug-development, unrelated to rare diseases or healthcare, reviews other than systematic reviews for health technology assessment. RESULTS: A total of 2513 unique references were obtained, and screened by title and abstract according to exclusion criteria. After exclusion, 308 references remained for full evaluation. Of those, 124 references described or proposed methods or policies for decision analysis and evaluation of orphan drugs. Additionally, 121 references described pharmacoeconomic or HTA evaluations, and 63 evaluated the budget impact or economic burden of rare diseases and their treatments. CONCLUSIONS: There is a global consensus of a need to develop appropriate methodology, analysis techniques, and related policies to address management of expensive treatments. It is not yet clear how best to evaluate the value of orphan drugs. More thorough evaluation and validation of novel modeling techniques, analytic rationale and proactive policy changes are needed to redefine the status quo of HTA relating to rare disease treatments.