The protein ICAM-3, also known as CD50, is a member of the intercellular adhesion molecule (ICAM) family consisting of three members. It is a DC-SIGN ligand that is constitutively expressed on resting leukocytes and is thus an important molecule for the first immune response. ICAM-3 comprises five immunoglobulin-like domains and binds LFA-1 through its two N-terminal domains. It functions not only as an adhesion molecule but also as a potent signaling molecule. ICAM-3 binds to LFA-1 on antigen-presenting cells (APC) stabilizing the T cell-APC interaction, facilitating signaling through the CD3/TCR complex. However, recent evidence using cultured and transformed T cells suggests ICAM-3 may also function in signaling. It has been reported that the CD50 molecule can play a role in developing functionally mature T lymphocytes and its expression increases during the maturation process of T lymphocytes. Also, the interactions of ICAM-3 and LFA-1 facilitate HIV-1- induced virological synapse formation between T cells. ICAM-3 is associated with an increase in cellular radio-resistance and cancer cell proliferation. It could be considered as a candidate for anti-cancer drug development and as a cancer diagnostic marker.