This article gives an overview of some of the ongoing challenges that are faced in the prevention, diagnosis and treatment of malaria. Malaria causes approximately 881,000 deaths every year, with nine out of ten deaths occurring in sub-Saharan Africa. In addition to the human burden of malaria, the economic burden is vast. It is thought to cost African countries more than US$12 billion every year in direct losses. However, great progress in malaria control has been made in some highly endemic countries. Vector control is assuming a new importance with the significant reductions in malaria burden achieved using combined malaria control interventions in countries such as Zanzibar, Zambia and Rwanda. The proportion of patients treated for malaria who have a confirmed diagnosis is low in Africa compared with other regions of the world, with the result that anti-malarials could be used to treat patients without malaria, especially in areas where progress has been made in reducing the malaria burden and malaria epidemiology is changing. Inappropriate administration of anti-malarials could contribute to the spread of resistance and incurs unnecessary costs. Parasite resistance to almost all commonly used anti-malarials has been observed in the most lethal parasite species, Plasmodium falciparum. This has presented a major barrier to successful disease management in malaria-endemic areas. ACT (artemisinin-based combination therapy) has made a significant contribution to malaria control and to reducing disease transmission through reducing gametocyte carriage. Administering ACT to infants and small children can be difficult and time consuming. Specially formulating anti-malarials for this vulnerable population is vital to ease administration and help ensure that an accurate dose is received. Education of healthworkers and communities about malaria prevention, diagnosis and treatment is a vital component of effective case management, especially as diagnostic policies change. Preventing resistance emerging to both ACT and insecticides used in vector control remains an ongoing challenge in an era of changing malaria epidemiology.