Malaria infects 5-10% of humanity and causes around two million deaths annually, mostly in children. The disease is of significant interest to immunologists, as acquired host immunity can limit the clinical impact of infection and partially reduces parasite replication; however, immunological reactions also contribute significantly to pathogenesis and fatalities. This review addresses the view that immunopathology in severe malaria arises predominantly from intravascular lesions resulting from a pathogen-initiated cascade of activated immune effector and regulatory cells infiltrating the vascular beds of diverse target organs, including bone marrow, spleen, brain, placenta and lungs. The main feature distinguishing these processes from classical cellular inflammation is the absence of extravasation, resulting from the intravascular location of the pathogen. Clinical and epidemiological observations combined with experimental infections in animal models suggest that parasite 'molecular patterns' or toxins cause cytokine and chemokine enhancement of infiltrates, composed of macrophages, neutrophils, natural killer (NK) cells, invariant natural killer T (iNKT) cells, gamma/delta T cells and both CD4(+) and CD8(+) effector T cells, leading to local vascular and organ derangement. Diverse pattern recognition and NK receptors crucially regulate these responding cell populations. Thus, innate immune mechanisms lie at the heart of this massive global public health problem.