The study of high-valent-iron enzyme intermediates began in the mid-1900s with the discovery of compounds I (or ES) and II in the heme peroxidases, progressed to non-heme-diiron enzymes in the 1990s with the detection and characterization of the Fe(III)-Fe(IV) complex, X, and the Fe(IV)-Fe(IV) complex, Q, in O(2) activation by ribonucleotide reductase R2 (RNR-R2) and soluble methane monooxygenase (sMMO), respectively, and was most recently extended to mononuclear non-heme-iron oxygenases with the trapping and spectroscopic characterization of the Fe(IV)-oxo intermediate, J, in the reaction of taurine:alpha-ketoglutarate dioxygenase (TauD). Individually, each of these landmark studies helped reveal the chemical logic of that particular enzyme system. Collectively, they have significantly advanced our understanding of Nature's strategies for oxidative transformation of biomolecules (both natural and "xenobiotic"). With high-valent complexes now having been described in representatives of three major classes of iron enzymes, it is an appropriate time to ask whether and what additional insights might be gleaned from further stalking of related intermediates in other systems. In this review, we advocate that there is still much to be learned from this pursuit and summarize the insight provided by two of the landmark discoveries mentioned above (the latter two) and the subsequent studies that they spurred to support our contention. In addition, we attempt to provide, to the extent that it is possible to do so, a "how-to" guide for detection and characterization of such intermediates, focusing primarily on enzymes in which they form by activation of molecular oxygen. In this latter objective, we have drawn from an earlier review by Johnson (Enzymes, third ed. vol. 20, 1992, pp. 1-61) covering, more generally, dissection of enzyme reaction pathways by transient-state kinetic methods. That work elegantly illustrated that, although it may be impossible to develop a true algorithm for the process, a synthesis of guidelines and general principles can be of considerable value.