OBJECTIVES: The popularity and availability of biomarkers has rapidly increased in recent years, thanks to innovative advances in pharmacogenomics. Predictive biomarkers have high potential value in HTA as they may increase the observed efficacy and cost-effectiveness of treatments. This study reviews, in selected major markets worldwide, the impact of currently available predictive biomarkers on HTA in the context of the agency’s evidence requirements. METHODS: A broad review of biomarker tests used in HTA submissions in Europe, Australia, Canada, and the US was conducted; the outcome of the HTA recorded and the impact of the biomarker test on the submission outcome was graded as high, medium or low according to its influence on the final decision. These findings were summarised, and 6 drugs were selected as case studies in order to identify key lessons relating to the risks, consequences, and ethical considerations of Diagnostic/Treatment partnering. RESULTS: The review identified five biomarkers in the five treatment areas of: HIV, Gastrointestinal stromal tumour (GIST), Non-small cell lung cancer (NSCLC), Colorectal cancer (CRC), and Breast cancer. Markers Her2 and K-RAS had a high impact in all included submissions, with 100% and 63% of these submissions resulting in a positive recommendation. In contrast, marker EGFR had a lower impact (not mentioned in 4 out of 10 submissions), with 60% of these submissions being approved, and 40% rejected. The agencies most likely to reject a surrogate-outcome submission were PBAC (Australia) and SMC (Scotland) with rejection rates of 57% and 66% respectively, whereas CADTH accepted 100% of included submissions. CONCLUSIONS: Findings indicate firstly that substantially different evidence requirements exist between HTA bodies in the markets considered (e.g. differing accuracy acceptability thresholds, prospective/retrospective analysis and the importance of cost effectiveness), and secondly there are several ethical considerations to the selection or deselection of patients for treatment.