Rare disorders are estimated to afflict more than 25 million Americans. US Congress passed the Orphan Drug Act of 1983 to provide financial incentives and accelerated FDA regulatory pathways to incentivize companies to develop much needed therapies to treat rare disorders. However, among the more than 7,000 rare disorders, majority of the disorders afflict fewer than 1,000 patients in the US. With “once-a-lifetime” treatment modalities such as gene therapy becoming the mainstay of rare disease treatments, a roadmap for innovative private-public partnerships to finance drug development will be helpful for underserved patient populations afflicted by ultra-rare diseases.