Aberrant expression of different family members of the Eph/ephrin system, which 
comprises the Eph receptors (Ephs) and their ligands (ephrins), has been 
implicated in various malignancies including breast cancer. The latter presents 
as a heterogeneous disease with diverse molecular, morphologic and clinical 
behavior signatures. This review reflects the existing Eph/ephrin literature 
while focusing on breast cancer heterogeneity. Hormone positive, HER2 positive 
and triple negative breast cancer (TNBC) cell lines, xenografts/mutant animal 
models and patient samples are examined separately as, in humans, they represent 
entities with differences in prognosis and treatment. EphA2, EphB4 and EphB6 are 
the members most extensively studied in breast cancer. Existing research points 
to the potential use of various Eph/ephrin members as biomarkers for assessing 
prognosis and selecting the most suitable therapeutic strategies in variable 
clinical scenarios, also for overcoming drug resistance, in the era of breast 
cancer heterogeneity.