Cocaine- and amphetamine regulated transcript (CART) is a recently discovered anorexigenic peptide, widely expressed in the central nervous system. Included among presumed hypothalamic mediated functions of CART are inhibition of food intake, stimulation of energy expenditure and regulation of hypothalamic–pituitary axes. CART-immunoreactive (IR) axons densely innervate the majority of hypophysiotropic thyrotropin-releasing hormone-(TRH) containing neurons in the hypothalamic paraventricular nucleus (PVN) and establish asymmetric synaptic specializations with the TRH neurons. The CART-IR innervation of TRH neurons originates from at least two major sources: CART neurons in the arcuate nucleus that co-express the anorexigenic peptide, alpha-melanocyte-stimulating hormone (α-MSH), and adrenergic CART neurons in the medulla. Based on the origins of the CART innervation and potent stimulatory effects of CART on TRH gene expression of hypophysiotropic neurons, CART is suggested to be involved in the regulation of the hypothalamic–pituitary–thyroid (HPT) axis by different physiological stimuli. This regulatory control may contribute to the effects of fasting and cold exposure to reset the set point for feedback regulation of hypophysiotropic TRH gene expression and hence, affect circulating thyroid hormone levels. In addition, CART is present in the majority of hypophysiotropic TRH neurons and in TRH-containing axon terminals adjacent to the capillary vessels in the median eminence. While CART, alone, has no effect on the TSH and prolactin secretion from anterior pituitary cells, CART inhibits the stimulatory effect of TRH on prolactin secretion, but has no effect on TRH-induced increase of TSH release. Co-secretion of CART with TRH into the portal pituitary circulation, therefore, may have an important modulatory influence on the effect of TRH on pituitary hormone secretion.