Proopiomelanocortin (POMC) is processed in an intracellular secretory pathway, primarily to enable release of adrenocorticotropic hormone (ACTH) from the pituitary and -melanocyte stimulating hormone (-MSH) from hypothalamic neurons and skin. However processing is incomplete and unprocessed POMC is secreted from all three tissues. This review considers intracellular processing of neuronal POMC as a key checkpoint that controls flux through hypothalamic melanocortin receptor (MC-R) pathways. Regulation of the convertase, PC1/3, which cleaves POMC is likely to determine the extent of POMC processing. Reduced PC1/3 activity, in both humans and rodents, leads to reduced melanocortin signalling and hence obesity. In contrast to POMC, post-translational processing of pro-agouti related peptide (pro-AGRP), an endogenous MC-4R antagonist, is efficient and is unlikely to represent a regulatory checkpoint. As POMC is fully processed to ACTH and MSH peptides in secretory vesicles, unprocessed POMC which is released from cells, must exit via an unregulated constitutive pathway. Therefore the targeting of POMC to secretory granules controls the extent of POMC cleavage. There is evidence that PC1/3 is involved in cleavage of POMC in the trans-Golgi network (TGN) and in regulating trafficking to the secretory pathway, where it subsequently cleaves POMC to the melanocortin peptides. This would suggest that -MSH and -MSH may be subject to alternative sorting mechanisms, leading to heterogeneity in secretory granule content in POMC producing cells. Overall, these studies implicate POMC processing as a key regulatory mechanism in the control of energy homeostasis.