OBJECTIVES: Most of the neuroanatomical models of bipolar disorder (BD) propose a key role for the anterior cingulate cortex (ACC). We provide here a review of currently available data regarding the CC neuroimaging and neuropathological alterations in BD. MATERIALS AND METHODS: After an exploratory search of the MEDLINE, we first identified all English-written articles that provide separate data for BD patients and report original experimental data on cingulate gyrus. Subsequently, we selected those including neuroimaging or neuropathological data. Among the 161 articles updated through June 2007, 81 articles were retained using this procedure. RESULTS: The review of in vivo volumetric imaging data, as well as ex vivo morphometric and histological studies indicates that BD patients show volume changes of the subgenual ACC (sgACC-BA 25 and part of 24) during the early stages of the disease. Whether this phenomenon is due to neuronal and glial depletion or damage of corticocortical connections is still a matter of debate. The resting state activity in the left BA 25 appears to be state dependent showing significant increase during mania and decrease during depressive phases. The presence of a deficient GABAergic activity in ACC is also documented. Pharmacological treatment partly restores BD-related functional imaging changes. CONCLUSION: The present review reveals the striking discrepancies of the experimental results present both for functional and structural imaging studies but also for neuropathological analyses. Methodological and conceptual limitations are addressed with particular reference to the heterogeneity of BD clinical patterns. We also critically discuss the validity of CC changes as possible trait- or state-markers of the disease.