Abstract: Protein phosphatases are a class of enzymes that can dephosphorylate proteins, as opposed to the phosphorylation function of protein kinases, which together regulate the phosphorylation levels of various proteins in cells and play an important role in cellular signaling transduction. Recent studies have shown that dysregulation of some protein phosphatases is implicated in the etiology of a variety of major human diseases such as cancer, diabetes, and autoimmune diseases. In contrast to the extensive study of protein kinases, the understanding of the regulatory mechanism of protein phosphatase still remains insufficient. In addition, it is quite challenging to identify highly potent and selective small molecule inhibitors of protein phosphatases as chemical probes. Therefore, the development of new therapeutic drugs of protein phosphatases to treat human diseases has long been hampered. In recent years, a number of small molecule allosteric inhibitors functioning outside the catalytic site of protein phosphatase have been reported, bringing new insight to the research of protein phosphatase inhibitors. The progress of these new protein phosphatase allosteric inhibitors is summarized, focusing on the small molecule inhibitors related to human diseases with clear acting site, and their discovery processes are also introduced briefly, so as to inspire more creative work on protein phosphatase allosteric inhibitors.