Malaria, a widespread disease caused by protozoa of the genus Plasmodium, contributes to the death of more than 2 million people each year. Resistance to antimalarial drugs is increasing, and an effective vaccine has not yet been designed. In the search for alternative means to control malaria infections, especially those caused by the most lethal species of malaria parasite, Plasmodium falciparum, our attention has turned to elucidating the relationships of the parasite and human host at the molecular level. In this review, we describe possible mechanisms by which naturally occurring genetic mutations might confer resistance to P. falciparum and how our innate immune response mediated by the phagocytic action of monocytes and macrophages acts as a first-line defence in clearing malaria infections. The potential effectiveness of novel therapies to enhance innate phagocytic clearance of malaria parasites, particularly in nonimmune people who are at greatest risk of adverse outcomes, is also discussed.