Abstract: Lymphoid-specific tyrosine phosphatase (LYP) is a phosphatase that is encoded by protein tyrosine phosphatase non-receptor type 22 and is mainly distributed in lymphoid. In psychological condition, LYP inhibits T-cell receptor (TCR) signaling in association with C-terminal kinase (CSK). While in pathological condition, mutant LYP dissociates with CSK, which augments the inhibition of TCR signaling and leads to autoimmune diseases. Consequently, LYP is now considered as a new target of type I diabetes, rheumatic arthritis and Graves disease and some other autoimmune disorders. This review mainly focuses on the development of LYP inhibitors in their structures and activities.