Infertility rates for both females and males have increased continuously in recent years. Currently, effective treatments for male infertility with defined mechanisms or targets are still lacking. G protein-coupled receptors (GPCRs) are the largest class of drug targets, but their functions and the implications on therapeutic development for male infertility largely remain elusive. Nevertheless, recent studies have shown that several members of the GPCR superfamily play crucial roles in the maintenance of ion-water homeostasis of the epididymis, development of the efferent ductules, formation of the blood-epididymal barrier, and maturation of sperm. Knowledge of the functions, genetic variations, and working mechanisms of such GPCRs, along with the drugs and ligands relevant to their specific functions, provide future directions and elicit great arsenal for potential therapy development for treating male infertility.