How do malaria ookinetes cross the mosquito midgut wall?

The route taken by malaria ookinetes to cross the midgut wall of the mosquito vector has been (and continues to be) controversial. In this article, we attempt to reinterpret and integrate the apparently conflicting observations of the past using the recently proposed Time Bomb model of ookinete invasion as a unifying framework. We argue that parasite entry into the midguit epithelium is always intracellular, occurs at sites where multiple adjacent host cells converge, and that parasite exit from the midgut epithelium can occur by either an intracellular or intercellular route, depending on the manner in which invaded host cells are extruded from the midgut wall. We also propose a novel hypothesis, the Cellular Treadmill model, to explain the movement of ookinetes through multiple adjacent midgut cells.