The aim of this article is to illustrate the current status of computer-assisted method development and retention modelling. This study focuses on the successful method development of typical small pharmaceutical compounds (impurity profiling) and large therapeutic proteins. By choosing appropriate initial conditions, the method development can be performed in less than one day. However, for small molecules possessing different physicochemical properties, the conditions can be multifarious, while for biopharmaceuticals (for example, monoclonal antibodies [mAbs], antibody–drug conjugates [ADCs]), a generic method can easily be developed. In addition to retention modelling and optimization, the potential of simulated robustness testing is also demonstrated. Depending on the applied retention model, the impact of any change among six experimental parameters (tG, T, pH or ternary composition, flow rate, and initial- and final mobile phase compositions) on the separation can be assessed using a 26 or 36 type virtual factorial design. No additional experiments are required to perform the robustness evaluation. Finally, virtual method transfer between different chromatographic systems is demonstrated