While few organisms undergo significant changes in pressure over their lifetime, pressure is an attractive protein unfolding mechanism because, like temperature, it is completely understood physically and can be simulated computationally. Under very high pressures (1-3 kbar or 100-300 MPa), voids within a protein’s folded structure become unstable, causing the protein to unfold. The kinetics of unfolding are typically extremely slow, orders of magnitude slower than unfolding with denaturant or temperature, which allows the use of careful nuclear magnetic resonance measurements to map which residues change structure first and can sometimes find complex folding dynamics. This study showed that often intermediates can be detected as well as complete unfolding. This Recommendation is of an article referenced in an F1000 Faculty Review also written by Lisa J Lapidus.