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Cephalopods are nontraditional but captivating models of invertebrate neurobiology, particularly in evolutionary comparisons. Cephalopod olfactory systems have striking similarities and fundamental differences with vertebrates, arthropods, and gastropods, raising questions about the ancestral origins of those systems. We describe here the organization and development of the olfactory system of the common cuttlefish, Sepia officinalis, using immunohistochemistry and in situ hybridization. FMRFamide and/or related peptides and histamine are putative neurotransmitters in olfactory sensory neurons. Other neurotransmitters, including serotonin and APGWamide within the olfactory and other brain lobes, suggest efferent control of olfactory input and/or roles in the processing of olfactory information. The distributions of neurotransmitters, along with staining patterns of phalloidin, anti-acetylated α-tubulin, and a synaptotagmin riboprobe, help to clarify the structure of the olfactory lobe. We discuss a key difference, the lack of identifiable olfactory glomeruli, in cuttlefish in comparison to other models, and suggest its implications for the evolution of olfaction.