Malaria parasites are known to invade and develop in erythrocytes and 
reticulocytes, but little is known about their infection of nucleated erythroid 
precursors. We used an in vitro cell system that progressed through basophilic, 
polychromatic, orthochromatic, and reticulocyte stages to mature erythrocytes. 
We show that orthochromatic cells are the earliest stages that may be invaded by 
Plasmodium falciparum, the causative agent of fatal human malaria. 
Susceptibility to invasion is distinct from intracellular survival and occurs at 
a time of extensive erythroid remodeling. Together these data suggest that the 
potential for complexity of host interactions involved in infection may be 
vastly greater than hitherto realized.