OBJECTIVES: The study aims to review and compare orphan drug (OD) policies in the USA, EU, Japan and South Korea. METHODS: The OD policies (regulation and list of incentives) were extracted from the official websites of the regulatory authorities. RESULTS: USA was the first to implemented OD legislation in 1983, followed by Japan (1993), South Korea (1997), and the EU (2000). The prevalence threshold is the highest in the USA and the lowest in Japan. The rarity of the disease or the lack of profitability is the only criteria for granting orphan status in the USA. In the EU, Japan and South Korea high unmet needs should be demonstrated. Some non-rare conditions are eligible for orphan designation in Japan and South Korea. Development feasibility needs to be proven in Japan. Specific scientific assistance is available in all regions except South Korea. Market exclusivity is granted for 10 years in the EU and 7 years in the USA. Financial assistance through fees reduction is available in all geographies. All regions but the EU also provide fast track marketing authorization procedure. Tax credits and/or tax reduction for clinical development and special grant programs are available in the USA and Japan. Only in South Korea, products that have already obtained orphan designation in elsewhere can benefit from a partial exemption from dossier submission for orphan designation and market authorization.  CONCLUSIONS: OD regulation and incentives are similar by nature but differ in magnitude. It is unclear how the profitability criteria are applied in US as multiple orphan products are blockbuster. USA applies the mildest criteria for granting orphan status and provides the greatest financial support. The financial assistance is the most modest in the EU while exclusivity is the longest.  EU adds an additional layer at member state level.