Large-scale, unreplicated natural experiments (LUNEs) have a unique power to test hypotheses at ecologically realistic scales and have delivered insights of great power into cosmology, evolution and geology. Yet, LUNEs are relatively rare in the field of ecology and continue to meet resistance due to their lack of replication. However, in the vast majority of cases, large-scale experiments cannot be replicated for practical and ethical reasons. Here, we make the case that LUNEs have had a disproportionately positive effect on conservation policy and are a crucial next step in the extrapolation of our understanding of ecological processes from small-scale experiments to relevant scales, particularly in the context of the current “replication crisis” affecting many sciences. Greater inclusion of LUNEs in mainstream ecology will help humanity to solve global problems as human transformation of the planet accelerates in coming decades.