This report provides an overview of the epidemiological patterns of malaria in the Greater Mekong Subregion (GMS) from 1998 to 2007, and highlights critical challenges facing national malaria control programs and partners in effort to build on their successes as they move towards malaria pre-elimination and elimination as a programmatic goal. Epidemiological data provided by malaria programs show a drastic decline in malaria deaths and confirmed malaria positive cases over the last 10 years in the GMS. More than half of confirmed malaria cases and deaths recorded in the GMS occur in Myanmar, however, reporting methods and data management are not comparable between countries despite effort made by WHO to harmonize data collection, analysis and reporting among WHO Member States. Malaria is concentrated in forested/forest-fringe areas of the region mainly along international borders providing strong rationale to develop harmonized cross-border pre-elimination programs in conjunction with national efforts. Across the Mekong Region, the declining efficacy of recommended first-line antimalarials, eg artemisinin-based combination therapies (ACTs) against falciparum malaria on the Cambodia-Thailand border, the prevalence of counterfeit and substandard antimalarial drugs, the lack of health services in general and malaria services in particular in remote settings, and the lack of information and services targeting migrants and mobile population present important barriers to reach or maintain malaria pre-elimination programmatic goals. Strengthening networking between research institutions and non-government organizations will increase knowledge-based decision and action.