Volume electron microscopy at an inflection point: challenges and opportunities ahead

Abstract Volume electron microscopy (vEM) has the potential to transform cell biology in ways that parallel the impact of cryo-EM on structural biology. Enhanced focused ion beam SEM (eFIB-SEM), serial block-face SEM (SBF-SEM), multibeam SEM, plasma FIB-SEM and Array Tomography (AT) platforms can acquire data at scales and resolutions unthinkable a decade ago. Despite its promise, the field has yet to realise its full potential, not due to intrinsic technological limitations but to shortcomings in the surrounding infrastructure. Sample preparation science lags instrument capability, computational pipelines are ceiling-limited by data quality, model generalisation is constrained by insufficient training data, facility models are still finding their footing, and community standards for acquisition reporting and data archiving remain underdeveloped. We argue that vEM stands at a genuine inflection point, and that decisions made now on infrastructure will determine whether the technology fulfils its promise as a routine discovery platform. Toward this goal, a key reframing is needed: vEM’s unique contribution is not simply high-resolution 3D imaging, but a structural scaffold for 4D cell physiology, reading dynamic biological state from ultrastructural data across cell types and evolutionary scales. Specific examples illustrate the breadth of this opportunity and the preparedness gap that must be closed.