Our cover image for Biophysical Journal’s March 2 issue conceptually shows how the grand challenge of protein dynamics can be addressed using computational tools and AFM-based experiments at the single-molecule level. We are aware of the strengths and limitations of both approaches, and we aim to establish a research agenda where we can combine these to elucidate biomolecular processes at the single-molecule level with higher resolution and wider time scales even when increased complexities are dominant.