Thyrotrophin releasing hormone-degrading activity (TRH-DA) is present in plasma, hypothalamus, pituitary gland, liver and kidney of adults of several species. Each of these tissues contains more than one TRH-degrading enzyme but only one, pyroglutamate aminopeptidase, isolated from the blood, is a TRH-specific enzyme. The aim of this study was to describe the developmental pattern of TRH-DA in the plasma, hypothalamus and liver and the role of tri-iodothyronine (T3) in the development of TRH-DA in the rat. Based on the hypothesis that thyroid hormones stimulate plasma TRH-DA in adult rats, degradation of TRH was studied in hypo- or hyperthyroid rats induced by 6-n-propyl-2-thiouracil or T3 respectively. Tritiated TRH was incubated with plasma and homogenates of hypothalamus or liver. After separation of degradation products by thin-layer chromatography, the amount of degraded [3H]TRH (pmol/50 microliters plasma or homogenate) was taken as a comparative index of TRH-DA. Plasma TRH-DA was not detectable before day 9 while hypothalamic and hepatic TRH-DA was already active at birth. Furthermore, the maturation pattern of total TRH-DA was different in plasma compared with other tissues and T3 appeared to play a significant role in its development. The absence of plasma TRH-DA in the neonatal period, its special thyroid-dependent developmental pattern and the presence of a specific TRH-degrading enzyme in adult blood suggest a physiological regulatory role for this activity.