 Biomolecular recognition including binding of small molecules, peptids, and proteins to their target receptors plays a key role in cellular function and has been targeted for therapeutic drug design. However, the high flexibility of biomolecules and slow binding and desaciation processes have presented challenges for computational modelling. Here, we review the challenges and computational approaches developed to characterize biomolecular binding, including molecular docking, molecular dynamic simulations, especially enhanced sampling, and machine learning. Further improvements are still needed in order to accurately and efficiently characterize binding structures, mechanisms, thermodynamics, and kinetics of biomolecules in the future. This article was authored by Jinan Wang, a perboboterei, hungendu, and others.