CD26 is a 110-kDa surface glycoprotein with intrinsic dipeptidyl peptidase IV (DPPIV) activity that is expressed on various cell types and has many biological functions. An important aspect of CD26 biology is its peptidase activity and its functional and physical association with molecules with key roles in human immunological programs. CD26 role in immune regulation has been extensively characterized, with recent findings elucidating its linkage with signaling pathways and structures involved in T cell activation as well as antigen-presenting cell–T cell interaction, being a marker of disease behavior clinically as well as playing an important role in autoimmune pathogenesis and development. Through the use of various experimental approaches and agents to influence CD26/DPPIV expression and activity, such as anti-CD26 antibodies, CD26/DPPIV chemical inhibitors, siRNAs to inhibit CD26 expression, overexpressing CD26 transfectants, soluble CD26 molecules and proteomic approach, we have shown that CD26 interacts with structures with essential cellular functions in T cell responses. We will review emerging data that suggest CD26 may be an appropriate therapeutic target for the treatment of selected immune disorders.