These elements reshaped the risk–reward profile of rare disease development and established a model that continues to attract capital and strategic focus. This article, Part one of a four-part rare disease thought-leadership series, examines how that winning formula emerged and why it continues to underpin rare disease development and investment. Part two will explore the pricing and access landscape of rare disease assets in the US and key global regions. These findings underscore that rare disease development is not monolithic; execution risk depends heavily on disease biology, diagnostic infrastructure, and therapeutic modality. Beyond spinal muscular atrophy, multiple rare disease therapies have crossed the $1 billion annual sales threshold, including Soliris for PNH and Cerezyme for Gaucher disease.