Malaria parasites induce strong proinflammatory immune responses upon infection. These responses, driven largely by CD4+ Th1 cells, help the body to control malaria parasitemia. When excessive, inflammatory responses contribute to the pathology observed in malaria infection. Dendritic cells (DCs) are innate immune cells that activate Th1 cells in malaria infection via the secretion of the cytokine IL-12. It remains unclear precisely which components of malaria-infected red blood cells are responsible for activating DCs. In this study, Wu et al. set out to deconstruct malaria-infected red blood cells to determine the immunogenic components that induce production of the proinflammatory cytokines IL-12 and TNF-α from DCs. The authors suggest that parasite DNA complexed with protein is the main trigger for activation of DCs in malaria-infected red blood cells.