Apoptotic cell death is thought to play a crucial role in the manifestation of insulin- and non-insulin dependent diabetes mellitus. Therefore, apoptosis and apoptotic markers were studied in the rat endocrine pancreas to get insight into the possible life cycle of Langerhans islets. The islets were investigated at 13 time points between day E19 and 18 months. At each time point, histologic sections were treated with the direct fluorescein-labelled TUNEL method and immunostained for pancreatic hormones (glucagon, insulin), apoptotic promoters (Bak, Bax, Fas, Fas Ligand) as well as for the anti-apoptotic peptide Bcl-2. All tissue sections were investigated using confocal laser scanning microscopy under identical settings for semiquantitative estimation of staining intensity. TUNEL-positive cells occurred in all pre- or postnatal stages. The findings indicated a biphasic apoptotic activity in the endocrine pancreas during the lifetime of rats. The first phase began at E19 and peaked at P5 accompanied by a considerable increase in Bak fluorescence staining intensity, while the second phase began at P30 and peaked at 18 months with increasing amounts of Fas and FasL staining intensities in the islet cells. The presented in situ data may be important for understanding the increased age-related vulnerability of islet cells and for studies of isolated and cultivated rat islets.