OBJECTIVES: Orphan drugs are therapies for low prevalence or neglected diseases with high unmet need. Many drugs have received orphan status globally, and benefited from 5-10 year marketing exclusivity; reduced stakeholder evidence requirements with unmet need weighing heavily into health technology assessment (HTA) and reimbursement decision-making; and largely uncontested pricing. Given tightening health system budgets, the proliferation of high priced orphan drugs in the United States (US) and Europe (EU) have caused these therapies to come under increased scrutiny from HTA agencies and payers to demonstrate value. To gain insight into evolving market access requirements, we conducted a multimarket review of orphan drug HTAs and reimbursement decisions comparing them to top selling non-orphan drugs in the US and EU. METHODS: Global HTAs and coverage decisions for orphan and blockbuster drugs were characterized and compared based on health economic, clinical and other value-based requirements. An analysis of orphan drug pricing was also conducted where pricing was available.  RESULTS: More than 20 orphan drug HTAs were identified, including those for genetic and central nervous system disorders, cancer and cardiovascular disease. HTA agencies and payers scrutinized the robustness of clinical evidence and lack of comparator data. Cost-effectiveness was also often evaluated, though with relaxed ICER thresholds compared to non-orphan drugs. Failure of an orphan drug to meet historically accepted evidentiary thresholds have led some evaluators to grant conditional reimbursement, with the proviso that further supportive evidence must be provided, although outright reimbursement denial has become increasingly common.  CONCLUSIONS: Once considered “reimbursement-safe” for drug developers, to achieve unrestricted reimbursement from payers orphan drugs now face higher evidentiary hurdles that are increasingly similar to non-orphan drugs. New pharmaceuticals intent on achieving optimal market access as an orphan drug must factor the evolving requirements for demonstrating value into clinical and health economic evidence generation plans.