This chapter will focus on control systems theoretic analysis and synthesis that significantly expand the range of performance specifications and positioning capabilities of scanning probe microscopes (SPMs).We will present a systems theory framework to study fundamental limitations on the performance of one and two degree-of-freedom (DOF) control designs for nanopositioning systems. In particular, this chapter will present, compare, and analyze optimal-control methods for designing two-degree-of-freedom (2DOF) control laws for nanopositioning. The different methods are motivated by various practical scenarios and difficulty in achieving simultaneously multiple performance objectives of resolution, bandwidth, and robustness by tuning-based or shaping of open-loop-plants based designs. The analysis shows that the primary role of feedback is providing robustness to the closed-loop device whereas the feedforward component is mainly effective in overcoming fundamental algebraic constraints that limit the feedback-only designs. Experimental results indicate substantial improvements (over 200% in bandwidth) when compared to optimal feedback-only controllers.