Thyroid hormones (THs), primarily T4 and T3, are crucial for regulating metabolism and development in mammals. THs are produced by the thyroid gland and act on various target tissues, including the brain, liver, muscle, heart, and adipose tissue. Defects in TH synthesis, transport, metabolism, and nuclear action can lead to genetic and endocrine diseases. Recent advances in understanding TH action and the development of tissue- and receptor isoform-targeted thyromimetics have opened new avenues for treating metabolic disorders such as hypercholesterolemia, dyslipidaemia, non-alcoholic fatty liver disease (NAFLD), and TH transporter defects. The history of TH research dates back to the 19th century, with early discoveries of the essential role of iodine in thyroid function and the successful treatment of myxoedema with thyroid extracts. The identification of thyroid hormone receptors (THRs) and their genomic actions has provided insights into the molecular mechanisms of TH regulation. THRs are nuclear receptors that bind to DNA enhancer elements and regulate the transcription of target genes. T3, the more potent form of TH, binds to THRs with higher affinity and is primarily responsible for its genomic actions. THs regulate a wide range of metabolic processes, including lipogenesis, fatty acid β-oxidation, cholesterol synthesis, and glucose metabolism. In the liver, THs control these processes by regulating the expression of key genes involved in these pathways. In skeletal muscle, THs influence contractile function, metabolism, and thermogenesis. In the heart, THs modulate contractility, rate, and metabolism. In brown adipose tissue (BAT), THs stimulate thermogenesis and mitochondrial biogenesis. In white adipose tissue (WAT), THs regulate adipogenesis and lipolysis. Pharmacological applications of THs and their analogs are being explored for treating conditions such as hypercholesterolemia, obesity, NAFLD, and neurological disorders. Tissue-specific biomarkers suggest that TH function can vary across different tissues, necessitating targeted therapy. For example, THRβ-specific thyromimetics have shown promise in reducing hepatic steatosis in NAFLD models. Understanding the complex interactions between THs and metabolic processes in specific tissues may lead to more effective and targeted treatments for metabolic disorders.Thyroid hormones (THs), primarily T4 and T3, are crucial for regulating metabolism and development in mammals. THs are produced by the thyroid gland and act on various target tissues, including the brain, liver, muscle, heart, and adipose tissue. Defects in TH synthesis, transport, metabolism, and nuclear action can lead to genetic and endocrine diseases. Recent advances in understanding TH action and the development of tissue- and receptor isoform-targeted thyromimetics have opened new avenues for treating metabolic disorders such as hypercholesterolemia, dyslipidaemia, non-alcoholic fatty liver disease (NAFLD), and TH transporter defects. The history of TH research dates back to the 19th century, with early discoveries of the essential role of iodine in thyroid function and the successful treatment of myxoedema with thyroid extracts. The identification of thyroid hormone receptors (THRs) and their genomic actions has provided insights into the molecular mechanisms of TH regulation. THRs are nuclear receptors that bind to DNA enhancer elements and regulate the transcription of target genes. T3, the more potent form of TH, binds to THRs with higher affinity and is primarily responsible for its genomic actions. THs regulate a wide range of metabolic processes, including lipogenesis, fatty acid β-oxidation, cholesterol synthesis, and glucose metabolism. In the liver, THs control these processes by regulating the expression of key genes involved in these pathways. In skeletal muscle, THs influence contractile function, metabolism, and thermogenesis. In the heart, THs modulate contractility, rate, and metabolism. In brown adipose tissue (BAT), THs stimulate thermogenesis and mitochondrial biogenesis. In white adipose tissue (WAT), THs regulate adipogenesis and lipolysis. Pharmacological applications of THs and their analogs are being explored for treating conditions such as hypercholesterolemia, obesity, NAFLD, and neurological disorders. Tissue-specific biomarkers suggest that TH function can vary across different tissues, necessitating targeted therapy. For example, THRβ-specific thyromimetics have shown promise in reducing hepatic steatosis in NAFLD models. Understanding the complex interactions between THs and metabolic processes in specific tissues may lead to more effective and targeted treatments for metabolic disorders.