Many techniques for nanoscale investigation, even though developed in different areas which do not have anything in common in terms of motivation or objectives, pose problems that are remarkably similar. Many of these problems involve regulation or estimation of certain physical variables under constraints and various uncertainties. In many cases existing solutions are area specific, static or open-loop, which are often inadequate or costly. Feedback has been embraced by very few areas, for instance in scanning probe microscopy, where it has shown a significant impact; yet it still remains largely underused. In this talk, common issues that arise in many nanoscale studies will be abstracted, and feedback-based solutions that addresses them will be presented. Specifically, this talk will present the role of feedback in managing uncertainties in model parameters, environmental noise, other disturbances, and sensor noise; its role in managing complexities in terms of complex dynamics, multiple objectives, constraints and limitations, and noisy measurements; and its role in enabling new techniques and methods that are otherwise not possible. These aspects will be demonstrated on issues arising from areas of scanning probe microscopy, precision positioning, x-ray microscopy, and optical probing of biocellular motor-proteins.