Protein phosphatases are important in a sense that they regulate the phosphorylation level of various proteins and in turn many physiological processes. Aberration in a fine tune among protein phosphatases and their counterparts, protein kinases, results in various diseases. Hence, the inhibitors of these enzymes have gained importance in disease treatments. In recent years, some natural and synthetic compounds have shown promising activity for protein phosphatase inhibition. This review describes, in a brief, strategies used to design and synthesis various molecules having significant potential to inhibit some crucial protein phosphatases and also gives an overview of different kinds of protein phosphatase enzymes and their physiological significance.