Gas fermentation processes (using CO₂, CO, H₂, CH₄) have gained significant research and commercial interest in the last years due to their potential for carbon capture and sequestration. The small economic margins of these processes necessitate the use of large-volume bioreactors. For cost-effective gas delivery, we advise using pneumatically agitated bioreactors, like bubble column reactors, compared to traditional stirred-tank reactors. Although scale-up is conventionally done on an empirical and rule-of-thumb basis, rational methods are currently available. The most important one is the knowledge-driven scaling-up approach, wherein (CFD-based) hydrodynamic and kinetic models of large-scale bioreactors guide the design of representative lab-scale experiments. We suggest several future research directions to enhance the predictive capacity of these models and thereby accelerate scaling-up gas fermentation processes.