Adhesion-GPCRs are unusual, owing to their unique structure, comprising a large and complex extracellular domain composed of various common protein modules. Adhesion-GPCR family members are expressed ubiquitously; however the expression of each receptor is highly regulated and often restricted to specific cell types. The EGF-TM7 adhesion-GPCR subfamily members are predominantly expressed by leukocytes and involved in coordinating both the innate and acquired immune responses. Here we highlight some immunological insights in relation to EGF-TM7 proteins and other members of the adhesion-GPCR family.