Iron-sulfur proteins are found in all kingdoms of life and carry out some of the most kinetically challenging reactions in the biosphere. In this talk, I will discuss my group’s efforts to understand how the remarkable functions of these proteins derive from the unique electronic structures of their iron-sulfur clusters. Emphasis will be placed on the use of synthetic models to understand how iron-sulfur clusters—typically comprised of mid-valent, high-spin iron centers—perform chemistry reminiscent of low-valent iron, specifically in the binding and activation of π acids such as N2 and CO. The synthetic methodology underlying the research will be discussed, as will the mechanisms of electronic cooperation that enable small molecule activation.