Cadherins were originally defined as homophilic adhesion molecules, thought specifically to only bind to other cadherins. In contrast to this paradigm, an interaction between E-cadherin and an immune receptor, integrin αE(CD103)β7 was identified over a decade ago to demonstrate the first heterophilic interaction between cadherins and non-cadherin molecules. Recently, E-cadherin was also found to interact with another immune receptor, killer cell lectin like receptor G1 (KLRG1). Both KLRG1 and the integrin αE(CD103)β7 expression have been associated with lymphocyte functions whereas E-cadherin is critical for the formation and maintenance of cellular junctions. The binding of these immune receptors to E-cadherin is intriguing and opens new unanticipated avenues of research. Here we review the current knowledge on KLRG1, integrin αE(CD103)β7 and cadherins. We also discuss the potential consequences of the interaction between KLRG1 and/or integrin αE(CD103)β7 and cadherin on both the immune response and tissue organization.