Plasmodium cynomolgi
(
Pcy
), a simian malaria parasite, is a recent perfect example of emerging zoonotic transfer in human. This review summarizes the current knowledge on the epidemiology of natural
Pcy
infections in humans, mosquitoes and monkeys, along with its biological, clinical and drug sensitivity patterns. Knowledge gaps and further studies on
Pcy
in humans are also discussed. This parasite currently seems to be geographically limited in South-East Asia (SEA) with a global prevalence in human ranging from 0 to 1.4%. The
Pcy
infections were reported in local SEA populations and European travelers, and range from asymptomatic carriage to mild/moderate attacks with no evidence of pathognomonic clinical and laboratory patterns but with
Pcy
strain-shaped clinical differences. Geographical distribution and competence of suitable mosquito vectors and non-primate hosts, globalization, climate change, and increased intrusion of humans into the habitat of monkeys are key determinants to emergence of
Pcy
parasites in humans, along with its expansion outside SEA. Sensitization/information campaigns coupled with training and assessment sessions of microscopists and clinicians on
Pcy
are greatly needed to improve data on the epidemiology and management of human
Pcy
infection. There is a need for development of sensitive and specific molecular tools for individual diagnosis and epidemiological studies. The development of safe and efficient anti-hypnozoite drugs is the main therapeutic challenge for controlling human relapsing malaria parasites. Experience gained from
P. knowlesi
malaria, development of integrated measures and strategies—ideally with components related to human, monkeys, mosquito vectors, and environment—could be very helpful to prevent emergence of
Pcy
malaria in humans through disruption of transmission chain from monkeys to humans and ultimately contain its expansion in SEA and potential outbreaks in a context of malaria elimination.
Supplementary Information
The online version contains supplementary material available at 10.1007/s15010-022-01952-2.