This chapter presents a scheme of model predictive discrete-time sliding mode control (MPDTSMC) with proportional-integral (PI) sliding function and state observer for the motion tracking control of a nanopositioning system driven by piezoelectric actuators. One distinct advantage of the controller is that its implementation only requires a simple second-order model of the system, whereas it does not need to know the hysteresis model and the bounds on system uncertainties. The reasons why the model predictive control methodology and PI action can eliminate the chattering effects and produce a low level of tracking error are addressed in the state-space framework. Experimental investigations are carried out to verify the feasibility of the control scheme.