OBJECTIVES: 1) Perform a comprehensive review of the US molecular testing environment; 2) Infer from results: Diagnostic/treatment areas most likely to include comparative effectiveness reviews (CER) involving molecular testing, how CER will be shaped by molecular diagnostics, evidence used in coverage decisions; and 3) Determine global generalizability of US trends.  METHODS: We reviewed: 1) All non-perinatal molecular tests with actual or potential for CER interface, all Medicare national (NCDs) and selected local coverage decisions (LCDs) involving molecular tests and CER, and US government and related agency high priority disease areas for CER, assessing actual or potential molecular testing inclusion, and 2) We inferred: Clinical areas most likely involving molecular diagnostics and CER,iImpact of molecular testing on CER, evidence required for Medicare/other payer coverage, and universality of US findings. RESULTS: 1) Inventory indicates 442 molecular tests/combinations of interest;  259 have potential degrees of CER interface; 2) Medicare database yielded: 2 NCDs (Screening DNA Stool Test for Colorectal Cancer, Pharmacogenetic Testing for Warfarin Response), 9 LCDs and articles: many denials of molecular test coverage, denials cite lack of evidence, including trials, clinical utility, and few cite cost-effectiveness data; 3) Five governmental or health technology assessment organizations point to 14 clinical areas as highest CER priorities: six known to have associated molecular tests; 5 already involved CER activity, and another 7 predicted to have future molecular testing and CER activity per identified priority areas for research. CONCLUSIONS: Expect molecular testing: to play an increasing future role in CER, particularly in 7 areas (cancer and hematopathology most prominently, inclusion will necessitate more methodologically sophisticated CER, will make cost-effectiveness part of CER, will require strong clinical utility evidence for payer coverage, and trends will be universal and more pronounced ex-US.