Despite its widespread acceptance, cost-effectiveness analysis, which examines an intervention’s incremental cost per unit of health gained, can run up against intuition in the context of drug coverage for conditions affecting special populations. In particular, the “rule of rescue” (i.e., spending more for populations perceived to be in immediate and great peril) may be justified for certain conditions. Examples include rare diseases and the “orphan drugs” used to treat them; cancer, with its attendant societal dread; and pediatric conditions, which are often inherited and severe. Cell and gene therapies may also challenge traditional value assessment, given their high manufacturing costs and potential for one-time, curative treatment. Health technology assessment (HTA) bodies worldwide have made exceptions for these populations by comparing cost-effectiveness ratios to higher (less stringent) benchmarks and by incorporating additional value considerations. Still, evaluating these higher-priced therapies remains a challenge for HTA and society.