Recent demonstrations of nanoscience provide ample evidence indicating the feasibility of rational control, manipulation and interrogation of matter at the atomic scale. A class of devices, with micro-sized sensor probes, called Scanning Probe Microscopes (SPMs) are in the forefront of the technology that have demonstrated imaging and manipulation of sample properties. However, this technology is still far from realizing the promise of routinely tailoring matter at the atomic scale. Such an ability, once realized, will have far reaching impact and revolutionize every area of science and technology, especially the areas of material science, biology, medicine, and manufacturing. This thesis presents control systems theoretic analysis and synthesis of new modes of operations that significantly expand the range of performance specifications and capabilities of SPMs. In particular, the focus of this thesis is on the two main requirements of SPMs, the precision positioning of the matter with respect to the probe and the obtaining of the surface topography from the probe data. A characterization of the inherent fundamental trade-offs between resolution, tracking-bandwidth, and reliability specifications on the positioning capability of these devices. A series of control designs which exploit these trade-offs appropriately to achieve pre-specified feasible performance objectives is discussed. These designs have two degrees of freedom (2DOF), that is, have the feedforward and the feedback components, and are obtained using the optimal control framework. Implementations and experimental results on the application of these designs show over 100-300% improvement over competing existing designs. For imaging, control systems tools have been used to model and analyze probe-sample (matter) interactions and design signals that estimate the sample topography. The central concept in this design is to view sample-topography signals as disturbance signals and use system theoretic tools to estimate them. Experiments using these estimate signals show substantial improvements in imaging and detection bandwidths, and fewer artifacts and misinterpretations in SPM imaging.