Despite the notion that computational fluid dynamics (CFD) models are considered complicated, expensive, time-consuming and difficult to formulate, their implementation offers an advanced prospect to move beyond empirical models, which inherit severe limitations in terms of flexibility, scale-up, and optimization of slurry bubble column reactors (SBCRs). This is because complex hydrodynamics coupled with chemical reactions in such reactors increase the uncertainty in using empirical models, leading to significant startup delays and overruns. Recent work by Basha et al. has shown that properly validated CFD models provide an exceptional opportunity to gain detailed temporal and spatial information about the local hydrodynamics and overall behavior as well as performance of SBCRs. This chapter provides a comprehensive overview of different CFD frameworks which could be used to model SBCRs, namely the multi-Eulerian, direct numerical simulations (DNS) and large Eddy simulation (LES). The steps required in developing CFD models and the optimization of different sub-models, such as interphase interactions, solid-phase representation, bubble population balance, bubble-induced turbulence, mass transfer and reaction kinetics are highlighted. Different convergence criteria for meshing, solution stability and techniques for maximizing the CFD model scale without compromising accuracy are addressed. An example of using CFD multi-Eulerian frameworks to describe the local hydrodynamics in a pilot-scale SBCR (0.3-m ID, 3-m height) operating under the Fisher-Tropsch (F-T) synthesis process are also provided.