A hallmark of Plasmodium development inside its mammalian victim is the remarkable restriction to the host species. Adaptation to an intracellular life style in specific target cells is determined by multiple parasite-host interactions. The first line of crosstalk occurs during intradermal sporozoite injection by an Anopheles mosquito. The following expansion in the liver is highly efficient and leads to successful establishment of the parasite population. During the periodic waves of fevers and chills the parasite destroys and re-infects red blood cells. Recent advances in experimental genetics and imaging techniques begin to expose the complex interactions at the changing parasite-host interfaces. Understanding the cellular and molecular mechanisms of target cell recognition, nutrient acquisition, and hijacking of cellular and immune functions may ultimately explain the elaborate biology of a medically important single cell eukaryote.