G protein coupled receptors (GPCR) have proven a treasure trove for modern pharmacological intervention of numerous human ailments. However, in stark contrast to classically targeted GPCRs, adhesion GPCRs habe been largely neglected by biologists, pharmacologists and clinician scientists for decades. Only recently their physiological and signaling properties are being unravelled and show exciting features including their roles in tissue architecture, signaling through tethered agonism and their unusual activation through mechanical cues. This seminar will discuss the recent developments on adhesion GPCR signaling and introduce the receptor family as a topical area in neuroscience and cancer research.