Recently licensed cell and gene therapies have promising but highly uncertain clinical benefits. They are entering the market at very high prices, with the latest entrants costing hundreds of thousands of dollars. The significant long-term uncertainty posed by these therapies has already complicated the use of conventional economic evaluation approaches such as cost-effectiveness and cost-utility analyses, which are widely used for assessing the value of new health interventions. Cell and gene therapies also risk jeopardising healthcare systems' financial sustainability. As a result, there is a need to recalibrate the current health technology assessment methods used to measure and compensate their value. In this paper, we outline a set of technical adaptations and methodological refinements to address key challenges in the appraisal of cell and gene therapies' value, including the assessment of efficiency and affordability. We also discuss the potential role of alternative financing mechanisms. Ultimately, uncertainties associated with cell and gene therapies can only be meaningfully addressed by improving the evidence base supporting their approval and adoption in healthcare systems.