Cilium and flagellum beating are important in reproduction and defects in their motion are associated with ectopic pregnancy and infertility. Adrenomedullin (ADM) is a polypeptide present in the reproductive system. This report demonstrates a novel action of ADM in enhancing the flagellar/ciliary beating of human spermatozoa and rat oviductal ciliated cells. At the concentration found in the seminal plasma, it increases the progressive motility of spermatozoa. ADM binds to its classical receptor, calcitonin receptor-like receptor/receptor activity-modifying protein complex on spermatozoa. ADM treatment increases the protein kinase A activities, the cyclic adenosine monophosphate, and nitric oxide levels of spermatozoa and oviductal cells. Pharmacological activators and inhibitors confirmed that the ADM-induced flagella/ciliary beating was protein kinase A dependent. Whereas nitric oxide donors had no effect on sperm motility, they potentiated the motility-inducing action of protein kinase A activators, demonstrating for the first time the synergistic action of nitric oxide and protein kinase A signaling in flagellar/ciliary beating. The ADM-induced motility enhancement effect in spermatozoa also depended on the up-regulation of intracellular calcium, a known key regulator of sperm motility and ciliary beating. In conclusion, ADM is a common activator of flagellar/ciliary beating. The study provides a physiological basis on possible use of ADM as a fertility regulation drug.