Spontaneous pituitary tumors have been studied by light and electron microscopy in female C57BL/6J mice at 2½, 11, 15, 22, 23, 24 and 30 months. Tumors were evident macroscopically in greater than 50% of mice 22 months or older, and greater than 80% on microscopic evaluation. Active and hypertrophied mammotrophs were the predominant cell type within the tumors at 22--30 months, often totally filling large portions of the tumor mass. Exocytosis of secretory granules was extensive from the mammotrophs, but much less abundant from other parenchymal cells. Somatotrophs and gonadotrophs were also present, and appeared active and often strikingly hypertrophied. The tumors were characterized by disruptions of parenchymal and capillary integrity which resulted in the formation of large vascular lakes lined solely by tumor cells, generally mammotrophs. Apparent metastasis of tumor cells into the vascular lakes was also observed. In 11- and 15-month mice small tumors or pretumor foci were evident in some mice on microscopic evaluation, although they were not visible macroscopically. Their degree of development was somewhat variable, but they had essentially the same features as more advanced tumors in older mice. Pretumor foci were characterized by more moderate disruptions of parenchymal cell and capillary integrity; cellular hypertrophy, particularly of somatotrophs and gonadotrophs; and the presence of small vascular lakes. In 2½-month mice tumors could not be localized macroscopically or microscopically, and the pituitary was composed of well-defined cell cords and an intact capillary bed. However, small focal zones of capillary and tissue disruption were apparent occasionally in 2½-month mice. These findings indicate that the process of pituitary tumorigenesis in female C57BL/6J mice is initiated by midlife, with subsequent progressive development into large, mammotroph-dominated tumors.