Thyroid hormones (THs) are essential for regulating development and metabolism in mammals. They act on various tissues including the brain, liver, muscle, heart, and adipose tissue. Defects in TH synthesis, transport, metabolism, and nuclear action are linked to genetic and endocrine diseases. Recent advances in understanding TH action and the development of tissue- and receptor-targeted thyromimetics have opened new possibilities for treating metabolic disorders such as hypercholesterolemia, dyslipidaemia, non-alcoholic fatty liver disease (NAFLD), and TH transporter defects. This review summarizes the historical development of TH understanding, its physiological and pathophysiological effects on metabolism, and future therapeutic applications. THs are produced by the thyroid gland and include T3 and T4. Their discovery and characterization have been pivotal in understanding their role in metabolism. THs regulate gene expression and metabolism through nuclear receptors, with T3 being more potent. THs influence various metabolic processes, including lipogenesis, fatty acid β-oxidation, cholesterol synthesis, and glucose metabolism. They also affect the liver, skeletal muscle, heart, brown adipose tissue (BAT), and white adipose tissue (WAT), playing key roles in energy homeostasis and metabolic regulation. THs have both genomic and non-genomic actions. Genomic actions involve gene transcription, while non-genomic actions include direct effects on cellular processes without DNA binding. THs regulate metabolism in various tissues, including the liver, skeletal muscle, heart, and adipose tissues, by modulating gene expression, mitochondrial function, and energy utilization. THs are involved in the regulation of metabolic disorders such as hypercholesterolemia, obesity, and NAFLD. TH analogs and thyromimetics are being developed for targeted therapy. These include compounds that selectively target specific tissues or TH receptors, showing promise in treating metabolic diseases. THs also play a role in neurological disorders, with mutations in TH transporters leading to conditions like Allan-Herndon-Dudley syndrome. TH analogs have shown therapeutic potential in improving neurological symptoms. In conclusion, THs are crucial for regulating metabolic and physiological processes. Understanding their complex roles in different tissues and their interactions with the environment and hormones is essential for developing effective therapies. Future research may focus on tissue-specific delivery and isoform-specific targeting of THs and thyromimetics to treat metabolic disorders more effectively.Thyroid hormones (THs) are essential for regulating development and metabolism in mammals. They act on various tissues including the brain, liver, muscle, heart, and adipose tissue. Defects in TH synthesis, transport, metabolism, and nuclear action are linked to genetic and endocrine diseases. Recent advances in understanding TH action and the development of tissue- and receptor-targeted thyromimetics have opened new possibilities for treating metabolic disorders such as hypercholesterolemia, dyslipidaemia, non-alcoholic fatty liver disease (NAFLD), and TH transporter defects. This review summarizes the historical development of TH understanding, its physiological and pathophysiological effects on metabolism, and future therapeutic applications. THs are produced by the thyroid gland and include T3 and T4. Their discovery and characterization have been pivotal in understanding their role in metabolism. THs regulate gene expression and metabolism through nuclear receptors, with T3 being more potent. THs influence various metabolic processes, including lipogenesis, fatty acid β-oxidation, cholesterol synthesis, and glucose metabolism. They also affect the liver, skeletal muscle, heart, brown adipose tissue (BAT), and white adipose tissue (WAT), playing key roles in energy homeostasis and metabolic regulation. THs have both genomic and non-genomic actions. Genomic actions involve gene transcription, while non-genomic actions include direct effects on cellular processes without DNA binding. THs regulate metabolism in various tissues, including the liver, skeletal muscle, heart, and adipose tissues, by modulating gene expression, mitochondrial function, and energy utilization. THs are involved in the regulation of metabolic disorders such as hypercholesterolemia, obesity, and NAFLD. TH analogs and thyromimetics are being developed for targeted therapy. These include compounds that selectively target specific tissues or TH receptors, showing promise in treating metabolic diseases. THs also play a role in neurological disorders, with mutations in TH transporters leading to conditions like Allan-Herndon-Dudley syndrome. TH analogs have shown therapeutic potential in improving neurological symptoms. In conclusion, THs are crucial for regulating metabolic and physiological processes. Understanding their complex roles in different tissues and their interactions with the environment and hormones is essential for developing effective therapies. Future research may focus on tissue-specific delivery and isoform-specific targeting of THs and thyromimetics to treat metabolic disorders more effectively.