Hypothalamic thyrotropin-releasing hormone (TRH) is the main positive regulator of thyrotropin (TSH) secretion. TRH action and the negative feedback of thyroid hormone are integrated in order to guarantee appropriate thyroid stimulation. TRH action affects various steps of the biosynthetic process within thyrotrophs, with major effects on the posttranslational maturation of TSH oligosaccharide chains, and is necessary for the secretion of the glycoprotein hormone with full biological activity. Since the first description in 1979 of some patients with central hypothyroidism of hypothalamic origin associated with the secretion of TSH molecules with conserved immunoreactivity but decreased bioactivity, a large body of evidence has accumulated in more recent years showing that changes of the oligosaccharide chains have a great impact on the biological properties of circulating TSH and occur in various in vivo situations. These findings have lead to the new concept of a qualitative regulation of TSH secretion. This can be achieved mainly through the transcriptional and posttranscriptional regulation of the complex enzymatic machinery devoted to the processing of the three oligosaccharide chains linked to specific asparagine residues of TSH heterodimer. Data obtained in several physiological and pathological conditions, which are characterized by an increased or diminished TRH action, indicate that both qualitative and quantitative regulations cooperate within thyrotrophs in order to adjust thyroid-stimulating activity to the temporary needs.