New emerging medicine classes offer transformational benefits (including gene and CAR-T cell therapies) for patients with severe unmet needs and will likely receive expedited marketing authorisation based upon promising, but very early clinical data. Appropriate reimbursement of these high-cost therapies will be very challenging under the traditional payer model. Further, frequently only a single treatment administration is required, necessitating substantial upfront investment. To manage these challenges, various innovative reimbursement and contracting approaches need to be implemented. The first FDA-approved CAR-T therapy (KYMRIAH) and gene therapy (LUXTURNA) announced innovative reimbursement strategies at launch, including performance-based reimbursement. Innovative reimbursement schemes have been previously attempted ex-US. In Australia, Managed Access Programmes allow the final reimbursed price to be determined post-launch based on ensuing data generation. However, post-establishment (2011), this has only been applied in three instances, none since 2014. A conditional reimbursement process for orphan drugs was established in 2006 in the Netherlands, enabling temporary reimbursement conditional on subsequent data. However, the first set of draft re-evaluation reports, concluding these were too expensive, led to a public backlash and these drugs were not delisted. In the UK, when Patient Access Schemes were first established, a variety of complex schemes were initially implemented but subsequently an almost universal preference for simple discount schemes exists. Many such reimbursement schemes have broad conceptual appeal but need to be carefully designed to deliver relevant information to mitigate payer risks. Payers are often not best-placed to design such schemes and therefore it is critical to involve appropriate stakeholders. In addition, notable failures in real-world implementation exist, due to lack of clinical efficacy of the drug and/or inability to provide relevant information for payers alongside increased associated management costs. These issues within single payer systems can be expected to be magnified applying to the more fragmented US system.