Recruitment and activation of monocytes and macrophages are essential for clearance of malaria infection, but these have also been associated with adverse clinical outcomes. In this review we discuss recent discoveries on how distinct molecular interactions between monocytes, macrophages, and malaria parasites may alter the balance between protection and pathology in malaria-infected individuals. The immunopathology of severe malaria often originates from excessive immune activation by parasites. The involvement of monocytes and macrophages in these events is highlighted, and priorities for future research to clarify the roles of these cells in malaria are proposed. Knowledge of the factors influencing the balance between protection and pathology can assist in the design of therapeutics aimed at modulating monocyte and macrophage functions to improve outcomes.