Background The concept of “efficacy-effectiveness gap” (EEG) has gained awareness in the scientific community and started to erode the confidence in decisions taken on drugs: authorization, appraisal, and medical choice between alternatives. The Innovative Medication Initiative was launched the GetReal project to tackle this issue. It gathers representatives of more than 14 pharmaceutical companies, public institutions such as EMA, HAS, ZIN, NICE and Academic research teams and aims at (1) better understanding how evidence of efficacy and effectiveness should be considered and reconciled and (2) proposing operational solutions. Objective and method We conducted a focused literature review to gain clarity and perspective on the concept of EEG: on which historical background it emerged, how it is understood and which solutions have been suggested to narrow it. Results A disconnect between outcomes from clinical trials and information needed for clinical practice has been identified in the process of standardization of drugs assessment (Schwartz, 1967), evidence-based medicine (Feinstein, 1997), and knowledge dissemination (Lehman, 1995), and called the EEG. Several factors have been identified to explain it, including characteristics of real-life healthcare settings (physician and patient behaviours) and the weak generalizability of clinical trials due to their design. The need for a more systematic assessment of effectiveness is now widely acknowledged. Adaptive licencing was recently proposed to account of the sequential evidence generation on drugs outcome (Eichler, 2011). The EEG can be conceptualized as the interaction of drug effect and “real-life” contextual factors (Unutzer, 1999). Conclusions Although the literature on the EEG is extensive, the contextual factors that actually impact drug’s outcome in real-life are still to be identified. Innovative and integrative study methods and designs are required to enable the EEG to be addressed adequately early on in the drug development process: this is the next step in the GetReal project.