The potential to deliver “one shot cures” is one of the most attractive aspects of gene therapy, genetically-engineered cell therapy and gene editing. However, such treatments offer a very different outlook with regard to recurring revenue versus chronic therapies, particularly in certain diseases where it is possible to cure a large proportion of the prevalent patient pool (or at least prevent an additional dose from being required for an extended period). While this proposition carries tremendous value for patients and society, it could represent a challenge for genome medicine developers looking for sustained cash flow. GILD is a case in point, where the success of its hepatitis C franchise has gradually exhausted the available pool of treatable patients. We highlight several potential solutions for these genome medicine companies to sustain an attractive profile. Solution 1: Address large markets: Hemophilia is a $9-10bn WW market (hemophilia A, B), growing at ~6-7% annually. We estimate that the hemophilia A market currently represents ~$6.5bn, while hemophilia B is ~$1.2bn. Solution 2: Address disorders with high incidence: Spinal muscular atrophy (SMA) affects the cells (neurons) in the spinal cord, impacting the ability to walk, eat, or breathe. It is the leading genetic cause of death in infants. SMA affects ~1 in 11k babies, and 1 in 50 individuals in the US is a genetic carrier. Cancer is also a sustainable market given the patient population is almost entirely incident driven. Solution 3: Constant innovation and portfolio expansion: There are hundreds of inherited retinal diseases (genetics forms of blindness). Once a gene therapy is approved for a genetic eye disease, the validated platform could be used to quickly develop many more eye-based gene therapies. Pace of innovation will also play a role as future programs can offset the declining revenue trajectory of prior assets.