As the need to prepare ever more complex but well-defined materials has increased, a similar need for reliable synthetic strategies to access them has arisen. Accordingly, recent years have seen a steep increase in the development of reactions that can proceed under mild conditions, in aqueous environments, and with low concentrations of reactants. To enable the preparation of well-defined biomolecular materials with novel functional properties, our laboratory has a continuing interest in developing new bioconjugation reactions. A particular area of focus has been the development of oxidative reactions to perform rapid site- and chemoselective couplings of electron rich aromatic species with both unnatural and canonical amino acid residues. This Account details the evolution of oxidative coupling reactions in our laboratory, from initial concepts to highly efficient reactions, focusing on the practical aspects of performing and developing reactions of this type. We begin by discussing our rationale for choosing an oxidative coupling approach to bioconjugation, highlighting many of the benefits that such strategies provide. In addition, we discuss the general workflow we have adopted to discover protein modification reactions directly in aqueous media with biologically relevant substrates. We then review our early explorations of periodate-mediated oxidative couplings between primary anilines and p-phenylenediamine substrates, highlighting the most important lessons that were garnered from these studies. Key mechanistic insights allowed us to develop second-generation reactions between anilines and anisidine derivatives. In addition, we summarize the methods we have used for the introduction of aniline groups onto protein substrates for modification. The development of an efficient and chemoselective coupling of anisidine derivatives with tyrosine residues in the presence of ceric ammonium nitrate is next described. Here, our logic and workflow are used to highlight the challenges and opportunities associated with the optimization of site-selective chemistries that target native amino acids. We close by discussing the most recent reports from our laboratory that have capitalized on the unique reactivity of o-iminoquinone derivatives. We discuss the various oxidants and conditions that can be used to generate these reactive intermediates from appropriate precursors, as well as the product distributions that result. We also describe our work to determine the nature of iminoquinone reactivity with proteins and peptides bearing free N-terminal amino groups. Through this discussion, we hope to facilitate the use of oxidative approaches to protein bioconjugation, as well as inspire the discovery of new reactions for the site-selective modification of biomolecular targets.