Abstract Existing systematic reviews of the health economic evidence for whole-exome and whole-genome sequencing (WES/WGS) are outdated or restricted to specific diseases or populations. This systematic review aims to provide an update on the health economic evidence for these sequencing options across a broad spectrum of clinical applications. We searched bibliographic databases (PubMed/EMBASE/MEDLINE/EconLit), the International Health Technology Assessment database, the Tufts cost-effectiveness analysis registry, and appraisals by the National Institute for Health and Care Excellence and the Scottish Medicines Consortium. We included studies reporting cost and/or cost-effectiveness results of WES and/or WGS, published between July 2016 and May 2024. Outcome-only studies were excluded. Summary information on study characteristics and findings was extracted, tabulated, and analysed. 130 studies were included. Availability of health economic evidence varied between geographic regions and clinical applications. 82 studies evaluated WES/WGS as diagnostic tools, but only five assessed prenatal, newborn, or healthy population screening. Many studies did not follow common methodological and reporting guidelines. Overall, WES/WGS can be cost-effective depending on the clinical and geographical context. The evidence base has grown significantly since 2016, but further evidence is needed, particularly for using these technologies for screening.