The tumor necrosis factor-α-induced protein 8-like (TNFAIP8, TIPE) family is recently identified proteins consisting of four highly homologous mammalian proteins: TIPE, TIPE1, TIPE2, and TIPE3. Although the four members share similar molecular structure and function, involving effects in pathophysiological processes of inflammation, immunity, tumors, stroke, angiogenesis, and other diseases, they have individual characteristics. Many studies have shown that TIPE2 is an essential negative regulator of both innate and adaptive immunity. Up-regulation of TIPE2 expression can alleviate excessive inflammation during septic shock and maintain hemostasis of macrophages, neutrophils, dendritic cells, T cells, and B cells. In this review, we summarize the current literature for structure feature, immune function, and regulatory mechanism of TIPE2, together with its clinical significance in the pathogenesis of immune disorders of a wide array of human diseases. Understanding the basic biology of this new molecule might help us to seek novel strategies for the immunomodulation of human diseases.