Top-down proteomics have recently started to gain attention as a novel method to provide insight into the structure of proteins in their native state, specifically the number and location of disulfide bridges. However, previous techniques still relied on complex and time-consuming protein purification and reduction reactions to yield useful information. In this issue of Proteomics, Zhao et al. (High throughput Screening of Disulfide-Containing Proteins in a Complex Mixture, Proteomics 2013) devise a clever and rapid method for high-throughput determination of disulfides in proteins via reduction by tris(2-carboxyethyl)phosphine. Their work provides the foundation necessary to undertake more complex experiments in biological samples.