Ultrastructural and immunocytochemical observations of pituitary folliculo-stellate cells (FSC) in a large series of adenomatous and nontumorous human pituitaries led to the following conclusions: (1) The endocrine cells of both the nontumorous and the adenomatous pituitary are capable of transforming into FSC while changing from endocrine to nonendocrine phenotype. (2) As shown on consecutive sections in prolactin cell adenomas with FSC-rich areas including microcyst formation, S-100 protein and glial fibrillary acidic protein (GFAP) immunoreactivities are strongest in the smallest newly formed follicles. The 2 immunoreactivities do not overlap. The epithelium of older microcysts is immunonegative, implying that expression of the 2 markers is restricted to the early phase of FSC formation. (3) Transformation of endocrine cells into FSC may signify retrodifferentiation into their Rathke's pouch derived precursors as suggested by occasional presence of ciliated and/or mucin producing cells in the lining of microcysts. (4) In lymphocytic hypophysitis a marked activation as well as increase of number and size of FSC are evident in areas of ongoing immune destruction supporting their immune role. (5) Considering the multifaceted nature of FSC, it is suggested that they represent a type of pluripotent adult stem cell.