Knowledge of the molecular ecology and environmental determinants of ammonia‐oxidizing organisms is critical to understanding and predicting the global nitrogen (N) and carbon cycles, but an incomplete biochemical picture hinders in vitro studies of N‐cycling enzymes. Although an integrative structural and dynamic characterization at the atomic scale would advance our understanding of function tremendously, structural knowledge of key N‐cycling enzymes from ecologically relevant ammonia oxidizers is unfortunately extremely limited. Here, we discuss the challenges and opportunities for examining the ecology of ammonia‐oxidizing organisms, particularly uncultivated Thaumarchaeota, through (meta)genome‐driven structural biology of the enzymes ammonia monooxygenase (AMO) and nitrite reductase (NirK).