The sporogonic cycle of Plasmodium falciparum was obtained in vitro. Mature gametocytes, from blood-stage cultures, produced gametes that underwent fertilization at elevated pH and ambient temperatures. Wheat germ agglutinin stimulated transformation of zygotes into retorts and ookinetes. Twenty-four hours thereafter, 18-49% mature ookinetes and 10-20% intermediate retort forms were counted. Cultures were seeded onto a basement membrane-like gel (Matrigel) in coculture with Drosophila melanogaster cells. Both ookinetes and retorts attached to Matrigel and transformed into oocysts. Mature oocysts and sporozoites expressed circumsporozoite protein. The entire life cycle of Plasmodium falciparum, the most important malaria pathogen of humans, can now be studied in vitro.