The mechanisms of action of thyroid hormone (TH), characterized by multiple physiological activities, proposed over the last 80 years are a reflection of the progression of our knowledge about eukaryotic signalling processes. The cumulative knowledge gained raises the question as to what is so special about the action of this hormone. The discovery in the 1980s that TH receptors belong to the family of nuclear transcription factors that regulate the expression of hormonal target genes was an important milestone. TH receptors are highly organized within the chromatin structure, which itself is modified by several chromosomal and nonchromosomal factors, in the presence and absence of the hormone. Recently, some investigators have suggested that TH acts via both genomic and nongenomic mechanisms and introduced the concept of networking within cellular complexes. While one cannot as yet precisely describe the mechanism of thyroid hormone action, I will attempt here to point out the present thinking and future directions to achieve this goal in the light of the historical background
