This article is a call for increased use of real-world evidence in health technology assessment and related policy and decision making. There is currently a disconnect between evidence used to guide regulatory approval of therapies and evidence used to inform therapeutic coverage and reimbursement decisions. Public and private payers need to understand not only whether an intervention works but also whether it offers good value compared with licensed alternatives (not placebo) as they are used in the real-world practice and population (not in a controlled trial environment). Addressing such concerns requires evidence to be drawn from a wide range of study designs, but with consideration and weighting given to their relative strengths and weaknesses, as well as their position on the pragmatic-explanatory (i.e., effectiveness-efficacy) continuum. The potential impact of using different types of evidence to inform cost-effectiveness analysis (CEA) is discussed for omalizumab, comparing and contrasting a CEA model informed by an omalizumab efficacy trial to a CEA model drawing primarily on evidence from effectiveness observational studies of omalizumab. There was reasonable agreement between the two omalizumab CEA models, although the incremental cost-effectiveness ratio generated by the effectiveness observational study-driven model was more favorable for omalizumab. Health technology assessment bodies and payers must use their judgment to determine which components of efficacy-based and effectiveness-based CEA evidence are most closely aligned with their goals. For each CEA evidence component, perhaps the two E's form bounds of the truth as well as a fuller picture of the uncertainty surrounding the truth.