Hypocretin/orexin (H/O) and melanin-concentrating hormone (MCH) are peptide neuromodulators found in separate populations of neurons located within the lateral and perifornical hypothalamic regions. H/O has been linked to sleep-wakefulness regulation and to the sleep disorder narcolepsy, and both systems have been implicated in energy homeostasis, including the regulation of food intake. In the present study we compared the development of H/O and MCH-expressing neuronal populations with in situ hybridization and immunohistochemistry on adjacent sections in the embryonic and postnatal rat brain. We found that MCH mRNA and protein were present in developing neurons of the hypothalamus by embryonic day 16 (E16), whereas H/O mRNA and protein were not detected until E18. We also identified previously undescribed populations of MCH-immunoreactive cells in the lateral septum, paraventricular hypothalamic nucleus, lateral zona incerta, and ventral lateral geniculate nucleus that may play a specific role in the development of these regions. MCH immunoreactive axonal processes were also evident earlier than H/O stained fibers and at the time H/O immunoreactive processes were first identified in the hypothalamus at E20, extensive MCH axonal fiber systems were already present in many brain regions. Interestingly, however, the density of axonal fibers immunoreactive for H/O in the locus coeruleus reached peak levels at the same developmental age (P21) as MCH immunoreactive axons in the diagonal band of Broca (DBB). The peak of axon density coincided with the developmental stage at which adult patterns of feeding and sleep-waking activity become established. The present results demonstrate developmental differences and similarities between the MCH and H/O systems that may relate to their respective roles in feeding and sleep regulation.