CD97 is a member of the adhesion G protein-coupled receptor (GPCR) family. It is widely expressed on, among others, hematopoietic stem and progenitor cells, immune cells, epithelial cells, muscle cells as well as their malignant counterparts. In the immune system, CD97 is known as a critical mediator of host defense. Upon lymphoid, myeloid cells and neutrophil activation, CD97 is upregulated to promote adhesion and migration to sites of inflammation. Moreover, it has been shown that CD97 regulates granulocyte homeostasis. Changes in the expression of CD97 have been described for auto-inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis. Outside the immune system, CD97 is likely involved in cell–cell interactions. CD97 is also expressed on many types of tumors including thyroid, gastric, pancreatic, esophageal, colorectal, and oral squamous carcinomas as well as glioblastoma and glioblastoma-initiating cells. In addition, enhanced CD97 expression has been found at the invasion front of tumors, suggesting a possible role in tumor migration/invasion, and correlated with a poorer clinical prognosis.