We have developed a high-pH, pH-shift refolding "Ph-Fold technology", both for academic research and industrial protein drug development applications. Using this technology, we were able to refold some "difficult-to-refold" proteins, some of which are proven important drug targets and protein drug candidates. The technology is composed of the initial E. coli production of inclusion bodies, the high pH solubilization/pH shift refolding screening technology, which includes automated pH shift refolding screening, and the methods of testing protein refolding without functional assay. This technology, especially the automated refolding system based on the Ph-Fold technology, may help both academic and industrial research in broadening structural genomic research, functional proteomics, and genomic scale drug development efforts.