Since the first case of Schistosoma mekongi infection was reported in 1957, control measures have been implemented in Laos and in Cambodia. Operational research provided the necessary information on parasite epidemiology and the associated morbidity in order to develop adequate control measures. S. mekongi transmission occurs in rocky banks of the river according to a seasonal cycle. Common daily activities of villagers living in the endemic areas constitute the risk factors for infection. The potential role of an animal reservoir is not fully understood. Severe disease is associated with advanced infection status. Signs and symptoms of portal hypertension dominate the clinical situation, and death is usually due to bleeding from ruptured esophageal varices. Schistosomiasis control in both Laos and Cambodia was based on universal treatment campaigns and resulted in a dramatic fall in the prevalence of the infection and in morbidity control. However, even if the disease and the infection have been satisfactorily controlled, transmission still occurs, and in very limited areas the prevalence reaches rates of more than 15%. Today, 60000 people are estimated to be still at risk of infection in Laos and about 80,000 in Cambodia. The new challenge in schistosomiasis control in endemic areas along the Mekong river is to consolidate the results, to establish a sensitive and reliable surveillance system, and finally to adapt control strategies to the low endemic situation. The impoverished nature of the region makes the possibility of sanitation unfeasible, and external support is still needed to sustain activities in the near future and to enable the substantial reduction of risk behaviors.