B7-H3 is a transmembrane glycoprotein and a member of the B7 family of proteins. It was previously known as an immunoregulatory molecule, shown in recent years to be of clinical significance in different types of cancer. In some tumor types high expression of B7-H3 has been linked to a poor prognosis, whereas in other cancers the opposite effect has been observed. Taken together, the precise role of B7-H3 in tumor immunity is unclear and further investigations are needed. Another aspect of B7-H3 that so far has received little interest is its role in non-immunological systems. We have demonstrated that knockdown of B7-H3 in melanoma and breast cancer cells results in both increased chemosensitivity and decreased metastatic potential. This has been observed in both in vitro and in vivo experiments. Several different signaling pathways seems to be involved, as B7-H3 knockdown can be linked to both higher expression of apoptotic markers and increased phosphorylation of Stat3. Increased knowledge of also the non-immunological role of B7-H3 protein is therefore of great biological and putative therapeutic interest.