The role of calcium in the invasion of human erythrocytes by Plasmodium falciparum merozoites has been investigated using a variety of techniques. It has been demonstrated using calcium-depleted medium that invasion is dependent upon the presence of calcium and that neither magnesium, manganese or zinc may substitute for it, suggesting that the effect is calcium specific and not dependent upon a non-specific, charge-based mechanism. Using resealed erythrocyte ghosts and altering the internal and external concentrations of calcium and the chelator EGTA, it has been shown that the role of calcium in invasion, at least as far as the target cell is concerned, is in the extracellular environment. Similarly, loading either the schizont-infected, or target erythrocyte with the membrane permeant calcium chelator Indo-1, at concentrations sufficient to chelate approximately 100 times the concentration of resting cell calcium, produced no change in the parasite invasion rate. Consequently we conclude that calcium plays an extra-cellular role in merozoite invasion of the human erythrocyte.