During the past century of research on the thymus, the fact that every mammalian thymus undergoes marked morphological changes during the complex process of aging has been defined as a basic histogenetical rule. In characterizing the physiological (i.e. chronic) involution of the mammalian thymus, the term "Altersinvolution" referring to age-related involution is used. All other types of thymic involution are associated with an initial trigger and a relatively "acute" mechanism. In all of these factor-dependent cases of thymic involution, we use the term "akzidentelle Involution" (i.e. acute accidental thymic involution). Temporary thymic involution occurs during pregnancy, with a full restoration of the cellular microenvironment at the end of lactation. It is now clear that pregnancy alters the well established adaptational homeostasis between the neuroendocrine and immune axes. Such nonprogressive involution has also been observed during various seasons in various animals (i.e. seasonal involution). Changes characteristic of thymic involution begin during or soon after the first year of birth, and continue progressively throughout the entire life span. The 3% to 5% annual reduction rate of the cells of the human thymic microenvironment continues until middle age, when it slows down to less than 1% per year. According to the extrapolation of these results total loss of thymic reticuloepithelial tissue and the associated thymocytes should occur only at the age of 120 years in humans. This serious reduction of the thymic cellular microenvironment is a well controlled physiological process and is presumably under both local and global regulation by the cells of the RE meshwork and the neuroendocrine system, respectively. In humans, the age related decline in serum "facteur thymique sérique" (FTS) levels begins after 20 years of age and FTS completely disappears from the blood between the 5th and 6th decade of life. In contrast, the serum levels of thymosin-alpha 1 and thymopoietin seem to decline earlier, starting as early as 10 years of age. The influences of a variety of other hormones on the involution of the thymus have also been characterized: testosterone, estrogen and hydrocortisone treatment results in marked involution, cortisone and progesterone administration causes slight to moderate, while use of desoxycorticosterone has no effect. The experimental administration of thyroxine yielded dose dependent results: low doses resulted in thymic hypertrophy, higher doses produced slight hypertrophy and the highest employed doses caused thymic atrophy. The atrophy was of apicnotic type, very different from that detected after treatment with corticoid hormones. Thymus transplantation experiments indicate that age-related, physiological thymic involution has been genetically preprogrammed. Grafting of the thymus from one week old C3H leukemic strain mice into 6 month old hosts resulted in changes in thymic weight and an involution pattern that was synchronous in all recipients, in direct correlation with the glands in the donor, but not in the host. These data strongly suggest that the stimulus for thymus cell proliferation and differentiation is genetically determined within the organ implant. Since the thymus is the primary T-lymphopoietic organ during ontogenesis in the mammalian organism, its age-related involution with the already mentioned morphological alterations can be held responsible only for a decline in antigen-specific T lymphocyte immune functions. Thymic involution and diminished T lymphocyte proliferation can be partially restored by thymic tissue transplantation or use of thymic hormones. The leading physiological role of the thymic cellular microenvironment as a "clock" of the mammalian aging process is also discussed. "If present cells have come from pre-existing cells, then all cells can trace their ancestry back to the first formed cell in an unbroken line of descent."--Rudolf Virchow, 1858(1) "I have neve