Orphan Drug Legislation incentivises the development of treatments for rare diseases that would otherwise not be profitable investment opportunities. However, with budgets squeezed and diseases increasingly stratified, we question whether this legislation is fit for purpose. Segmenting diseases into genetically-defined sub-groups, most notably among some cancers, has enabled increased pharmacological targeting. Common diseases are thus being reconsidered as multiple rare conditions, each eligible for orphan designation, entitling the treatments to the economic benefits afforded by legislation. Stratification also occurs in diseases which are already rare (e.g. cystic fibrosis), and new treatments, such as ivacaftor, are being developed to target specific mutations. Orphan status for a drug is maintained regardless of whether the overall population size, for which the drug is licensed, exceeds prevalence thresholds enabling companies to take a strategic approach to development. The high prices of orphan drugs impact on access.  However, typical cost-effectiveness thresholds are often waived suggesting that greater value is placed on treatments for rare conditions, compared with prevalent diseases that are equally severe and debilitating. Population surveys indicate that funding policies that take resources from elsewhere in health economy budgets to fund these treatments are not in the public interest. At the same time, research and development into certain common diseases such as stroke, where the burden is much higher, has been somewhat neglected. We believe it is time to revisit orphan drug legislation. Regulators should be able to limit the benefits of orphan designation should the cumulative eligible population exceed a certain threshold. More robust criteria need to be applied for defining a “medically plausible subset” and pricing should to be brought closer in line with drugs for non-rare diseases. Furthermore, the focus of incentives should move more towards areas of unmet need where disease burden is greatest.