The ability to sense and respond to various key environmental cues is important for the survival and adaptability of bacteria, including pathogens. The particular sensitivity of iron-sulfur (Fe-S) clusters has been exploited in nature through the evolution of multiple sensor-regulator proteins that use a sensing reaction at their Fe-S cluster to coordinate the detection of environment signals with (in many cases) a global transcriptional response. The fragility and sensitivity of these Fe-S clusters makes studying such proteins difficult, hampering efforts to determine what signals they sense, how they sense them, and how they transduce the signal to affect transcription. In this seminar, I will describe a number of Fe-S cluster regulators under study in my laboratory, and the approaches we have taken to gain structural and functional insight. In particular, I will describe the application of native mass spectrometry to studies of Fe-S proteins and the chemistry taking place at the cluster.