Latrophilins (LPHN) are part of a yet unexplored family of receptors comprising three isoforms, LPHN1-3, and belonging to a unique branch of G protein-coupled receptors (GPCR) named adhesion GPCR (aGPCR). LPHN are considered to be prototypical models for the study of aGPCR as they are one of the most evolutionary conserved members. Previously described as the target for a potent neurotoxin from the black widow spider venom, LPHN are now being studied under a whole new perspective. Indeed, recent advances have provided a better understanding of different aspects of this prototypical family of receptors: 1) elucidation of LPHN ectodomain organization by crystallography has unveiled a new functional domain with great repercussion on all the other members of the aGPCR family, 2) proteomic approaches have opened the gate to unsuspected functional characteristics of LPHN cellular role, and 3) genetic approaches have provided hints into the physiological functions of LPHN in specific systems and organisms. Moreover, genomic linkage studies screening human patients from diverse genetic backgrounds have involved LPHN gene defects in human disorders such as attention-deficit hyperactivity disorder and cancer. In this review, we will provide a historical perspective addressing experimental research on these receptors while highlighting the new advances and discoveries concerning LPHN functions. As GPCR still represent the most studied targets for the development of pharmacological approaches aiming at alleviating human disorders, the relevance of studying LPHN retains a high pertinence to better understand these receptors for the treatment of human diseases.