Abstract Chromatographic separations are an expanding technology for the separation of high value products, particularly in the area of pharmaceutics, food, and fine chemicals. The simulated moving bed (SMB) process as a continuous chromatographic separation process is an interesting alternative to conventional batch chromatography, and gained more and more impact recently. The SMB process is realized by connecting several single chromatographic columns in series. A countercurrent movement of the bed is approximated by a cyclic switching of the inlet and outlet ports in the direction of the fluid stream. Because of its complex dynamics, the optimal operation and automatic control of SMB processes is a challenging task. This paper presents the design of a model-based optimization and control scheme for SMB chromatographic separation processes and its application to the separation of fructose and glucose. We propose a two-layer control architecture where the optimal operating trajectory is calculated off-line by dynamic optimization based on a rigorous process model. The parameters of the model are adapted based on online measurements. The low-level control task is to keep the process on the optimal trajectory despite disturbances and plant/model mismatch. Here identification models based on simulation data of the rigorous process model along the optimal trajectory are combined with a suitable local controller. The efficiency of the trajectory control algorithm is shown in a simulation study for the separation of fructose and glucose on an 8-column SMB plant.