OBJECTIVES: The discovery of EGFR and ALK changes in non-small cell lung cancer (NSCLC) and the development of targeted therapies (TTs) directed against these mutations have revolutionized the treatment landscape. However, the added value of TTs is inextricably tied to the ability of a companion diagnostic (CDx) to identify patients who are likely to respond. Moreover, TTs and CDx are subject to different regulatory and market access frameworks at the European and national levels. The primary objective of this study was to compare the Health Technology Assessment (HTA) considerations for TTs and CDx in NSCLC in France, Germany, and England. Differences in access schemes were also explored. METHODS: A literature search of the EMA, national HTA agency, and institutional websites was performed to identify TTs-CDx pairings, their corresponding HTA evaluations, and patient access schemes. HTAs were assessed for key clinical, economic, or other criteria taken into account by the agencies. RESULTS: As of June 2016, seven TTs were identified for further analysis. NICE and IQWiG were more likely than HAS to issue a negative opinion or restrict the target population or treatment line. NICE guidance provided an integrated assessment including cost-effectiveness and discussion of the accuracy and availability of the CDx, whereas these aspects were assessed separately or not at all by HAS and IQWiG. Notable access schemes included the use of the Cancer Drugs Fund in England and the National Institute of Cancer’s diagnostic access program in France. CONCLUSIONS: There is a heterogeneous approach to HTA and access schemes for NSCLC TTs in France, Germany, and England. HAS may be more likely than NICE or IQWiG to grant wider access for treatments which other agencies consider to have insufficient evidence. Potential future developments such as a shift towards adaptive licensing and multi-biomarker tests could lead to increasingly divergent approaches.