Described are various embodiments of an ion beam delayering system and method, topographically enhanced sample produced thereby, and imaging methods and systems related thereto. In one embodiment, a method comprises: identifying at least two materials in an exposed surface of the sample and predetermined operational characteristics of an ion beam mill that correspond with a substantially different ion beam mill removal rate for at least one of the materials; operating the ion beam mill in accordance with the predetermined operational characteristics to simultaneously remove the materials and introduce or enhance a topography associated with the materials and surface features defined thereby; acquiring surface data; and repeating the operating and acquiring steps for at least one more layer.