Rare diseases are often heterogeneous in their progression and response to treatment, with only a small population for study. Challenges for evidence generation to support Health Technology Assessment (HTA) are especially profound in the case of rare disease drugs, thus requiring novel research methods. Discussion with an expert panel presented in an article published in International Journal of Technology Assessment in Healthcare explored differential approaches for HTA evidence generation for rare disease treatments. The experts informed, providing examples of case studies, that adaptive trial designs, trials analysed using Bayesian techniques, and disease specific patient reported outcomes as well as qualitative research to elicit patients’ perspectives are all of immense value to generate evidence for HTA. The authors emphasise the importance of international consensus and collaboration to agree on the how the value of products to treat rare diseases will be assessed in HTA.