OBJECTIVES: Assessing the economic value (EV) of orphan drugs (ODs) within the existing health technology assessment (HTA) framework is challenging. We therefore decided to evaluate current and alternative HTA approaches for ODs. METHODS: Published studies from 2000 to July 2014 focusing on methods for assessing the EV of ODs were identified via MEDLINE. A targeted search for recent HTA submissions was also performed, covering five ODs we selected as most relevant (bosutinib, brentuximab vedotin, everolimus, pomalidomide and ruxolitinib) across six European countries (France, Germany, Ireland, the Netherlands, Sweden and the UK). RESULTS: Eleven published papers were identified. All papers concluded that ODs are not suited to standard economic evaluations and the current HTA framework. The primary reasons were inadequate evidence of efficacy due to low patient numbers, lack of important outcome measures such as quality of life, no long-term outcomes data, and no information on the systemic impact of the disease beyond the health impact, i.e. financial, emotional and social. The inherent uncertainty regarding short- and long-term health gains combined with high acquisition costs leads to incremental cost-effectiveness ratios well beyond existing HTA thresholds. We identified alternative methods such as including societal value, emphasising burden of illness and using variable thresholds, weighted outcome measures, surrogate markers and alternative statistical approaches like Bayesian methods. However, none of these have been implemented in existing HTAs. We confirmed this in our review of HTAs, which also showed inconsistency in decisions taken by HTA bodies. CONCLUSIONS: Assessing EV of ODs remains a challenge. Despite being discussed in the literature, no innovative methods have been used in recent HTA submissions. HTA bodies, companies developing ODs, patients and society must engage in further discussions on how to assess value. Until then, considerable risk remains that access to ODs is unequal compared to non-ODs and across countries.