In this article, we propose an integrated approach to achieve high-speed nano-positioning for high-speed atomic force microscope (AFM) operations in applications such as probe-based nanofabrication. The development of AFM technology enabled the “bottom up” approach to design and create nanostructures and nanodevices. The throughput of the probe-based nanofabrication, however, is limited by the challenges in positioning the probe at high-speed. In AFM operations, nano-positioning of the probe in 3-D (both lateral x – y and vertical z axes) is needed. High-speed, large-size AFM operation is challenging because in high-speed lateral scanning of the AFM operation at large positioning range, large positioning error of the AFM probe relative to the sample can be generated due to the adverse effects—the nonlinear hysteresis and the linear vibrational dynamics of the piezotube actuator. In addition, vertical precision positioning of the AFM probe is even more challenging (than the lateral scanning) because the desired trajectory (i.e., the sample topography profile) is unknown in general, and the probe positioning is also effected by and sensitive to the probe-sample interaction. The main contribution of this article is the development of an integrated approach that combines advanced control algorithm with an advanced hardware platform. The proposed approach is demonstrated by implementing to AFM imaging of a large-size (50 μm ) calibration sample at high-speed (50 Hz scan rate).