It has been long suggested that Bipolar Disorder (BD) is associated with abnormalities within neural circuits encompassing subcortical-limbic-prefrontal structures. In addition, neuropathological studies have found that BD is not associated with a neurodegenerative pattern with gliosis. Instead, it appears that glial cells are reduced in certain brain areas such as the prefrontal cortex. Independent anatomical MRI studies have demonstrated that whole-brain and local gray matter content are negatively correlated with length of illness. However, most of these studies are cross-sectional in nature and longitudinal studies are still awaited. Nevertheless, considering that most of the gray matter signal captured with MRI relates to glial cell processes, MRI studies are consistent with the hypothesis of reduced glial support in BD. Further evidence supporting reduced glial function in BD comes from 1H-MRS and cell culture studies suggesting alterations in energy metabolism in the hippocampus and prefrontal cortex in individuals with BD. Finally, there is evidence from MRI studies showing that lithium increases gray matter content in bipolar subjects, which may be related to its ability to increase neurotrophic factors. Interestingly, recent studies have found that genetic modulation of gray matter content and hippocampal volume may be more pronounced in bipolar subjects, which suggests some form of vulnerability in BD. Methodological issues that may be relevant to the (in)consistencies observed in brain imaging studies in BD will be addressed.