According to their structure and sequence relationships, Ephrins can be divided into the ephrin-A (EFNA) class and the ephrin-B (EFNB) class. Ephrin receptors are the largest subgroup in the receptor tyrosine kinase (RTK) family. EphrinB type receptor 6 (EphB6) is an unusual Eph receptor that lacks catalytic ability due to changes in its kinase domain. EphB6 can regulate cell adhesion and migration in both positive and negative directions. Additionally, Ephrin-B2 may be a physiological ligand for the EphB6 receptor. In some tumor types, including breast cancer, the increase of metastasis activity is related to the decrease of EphB6 receptor expression, which indicates that EphB6 may be used as an inhibitor of cancer invasion. EphB6 inhibits cancer invasion through c-Cbl dependent signaling, morphological changes, and cell adhesion, indicating that EphB6 may be a useful prognostic indicator and therapeutic target.