The competitiveness of small modular reactors (SMRs) has been planned based on design simplification, short construction time, passive safety systems, and enabling self-financing by ramp-up construction. Due to the global energy challenges, SMRs have received pervasive attention from a wide range of researchers, designers, developers, stakeholders, and customers. Besides the many advantages related to the design of SMRs, there are challenges ahead of these reactors. SMR licensing is one of the most critical challenges in the front deployment of these reactors. This challenge stems from innovations in SMR designs and systems, such as modularity or deployment for desalination, energy storage, hydrogen production, process heat, and district heating. Due to the lack of experimental data and technical knowledge, the licensing challenges for non-water coolant SMRs are more complicated. Nearly all previous generation reactor licenses were based on conservative analysis while the decision-making methods based on best-estimate and realistic approaches have received more attention in recent years. Thus, the method known as the best estimate plus uncertainty (BEPU) approach is selected for licensing in some cases. At this time, using the BEPU approach in licensing for conventional NPPs is a mature technology and ready for industrial application. Nevertheless, because most previous reactors were licensed based on conservative methods, developers and even regulatory bodies resist re-assessments based on the BEPU approach, while using the choice of conventional conservative methods is a type of roll-back for next-generation SMRs. Thus, this work reviews the BEPU approach and clarifies the possibility of using this approach in the licensing process of SMRs. The lack of experimental data and tight coupling of phenomena along with uncertainty quantification are the main challenges ahead of using BEPU in the licensing process of SMRs.