In this Forum Article, an extensive discussion of the mechanism of six-electron, seven-proton nitrite reduction by the cytochrome c nitrite reductase enzyme is presented. On the basis of previous studies, the entire mechanism is summarized and a unified picture of the most plausible sequence of elementary steps is presented. According to this scheme, the mechanism can be divided into five functional stages. The first phase of the reaction consists of substrate binding and N-O bond cleavage. Here His(277) plays a crucial role as a proton donor. In this step, the N-O bond is cleaved heterolytically through double protonation of the substrate. The second phase of the mechanism consists of two protoncoupled electron-transfer events, leading to an HNO intermediate. The third phase involves the formation of hydroxylamine, where Argim provides the necessary proton for the reaction. The second N-O bond is cleaved in the fourth phase of the mechanism, again triggered by proton transfer from His(277). The Tyr(218) side chain governs the fifth and last phase of the mechanism. It consists of radical transfer and ammonia formation. Thus, this mechanism implies that all conserved active-site side chains work in a concerted way in order to achieve this complex chemical transformation from nitrite to ammonia. The Forum Article also provides a detailed discussion of the density functional theory based cluster model approach to bioinorganic reactivity. A variety of questions are considered: the resting state of enzyme and substrate binding modes, interaction with the metal site and with active-site side chains, electron- and proton-transfer events, substrate dissociation, etc.