To complete their life cycle, Plasmodium parasites must survive the environment in the insect host, cross multiple barriers including epithelial layers, and avoid destruction by the mosquito immune system. Completion of the Anopheles gambiae and Plasmodium falciparum genomes has opened the opportunity to apply high throughput methods to the analysis of gene function. The burst of information generated by these approaches and the use of molecular markers to investigate the cell biology of these interactions is broadening our understanding of this complex system. This review discusses our current understanding of the critical interactions that take place during the journey of Plasmodium through the mosquito host, with special emphasis on the responses of midgut epithelial cells to parasite invasion.