Thyroid hormone influences diverse metabolic pathways important in lipid and glucose metabolism, lipolysis and regulation of body weight. Recently, it has been recognized that thyroid hormone receptor interacts with transcription factors that predominantly respond to nutrient signals including the peroxisome proliferator-activated receptors, liver X receptor and others. Crosstalk between thyroid hormone signaling and these nutrient responsive factors occurs through a variety of mechanisms: competition for retinoid X receptor heterodimer partners, DNA binding sites and transcriptional cofactors. This review focuses on the mechanisms of interaction of thyroid hormone signaling with other metabolic pathways and the importance of understanding these interactions to develop therapeutic agents for treatment of metabolic disorders, such as dyslipidemias, obesity and diabetes.