G-protein coupled receptors (GPCRs) represent the most diverse and biologically ubiquitous protein receptors. The epidermal growth factor seven-span transmembrane (EGF-TM7) family consists of adhesion GPCRs with a diverse functional repertoire. CD97 is the most broadly expressed member with roles in cell adhesion, migration and regulation of intercellular junctions. CD97 is also expressed in a variety of human malignancies including those of the thyroid, stomach, colon and brain. CD97 confers an invasive phenotype and has been shown to correlate with tumor grade, lymph node invasion, metastatic spread and overall prognosis. More recently, CD97 was found to signal through G_12/13, resulting in increased RHO-GTP levels. Proven roles in tumor invasion and signaling make CD97 an exciting novel therapeutic target. In this review, we will discuss the structure and function of this receptor, with a specific focus on its mechanistic significance in neoplastic diseases.