<jats:sec><jats:title>Objective:</jats:title><jats:p> Cortical and subcortical gray matter abnormalities have been reported in individuals at high genetic risk for bipolar disorder, but the findings are inconsistent. The aim of this study was to review the available literature to identify common findings that could represent brain structural vulnerability factors for bipolar disorder and to discuss challenges for the advancement of the field. </jats:p></jats:sec><jats:sec><jats:title>Method:</jats:title><jats:p> A systematic search was conducted using the PubMed database to identify all original articles investigating cortical or subcortical gray matter abnormalities in first-degree relatives of bipolar disorder patients. </jats:p></jats:sec><jats:sec><jats:title>Results:</jats:title><jats:p> Very few findings were replicated, with the exception of larger insular cortex volumes in adult first-degree relatives and larger right inferior frontal gyrus in offspring of probands with bipolar disorder, both when compared with healthy controls. Isolated findings included decreased gray matter density in the left thalamus, decreased gray matter volumes in the left hippocampus and parahippocampal gyrus, and thicker right hippocampus in unaffected first-degree relatives. Genetic liability for bipolar disorder was associated with gray matter volumes in regions of the anterior cingulate cortex, ventral striatum, medial frontal gyrus, right precentral gyrus, right insular cortex, and medial orbital gyrus. Some studies found no evidence for gray matter abnormalities in first-degree relatives of bipolar disorder patients. </jats:p></jats:sec><jats:sec><jats:title>Conclusions:</jats:title><jats:p> Possible reasons for the discrepancies of findings across studies include small samples sizes, small effect size of susceptibility genes, the phenotypic heterogeneity of bipolar disorder, and the possible confounding effect of other Axis I psychopathologies among the relatives of patients. Future multisite, prospective, large studies with more homogeneous samples would be a key strategy to advance the field. The ultimate benefit would be an understanding of how to use brain imaging tools to identify individuals at increased risk for bipolar disorder and develop preventive strategies for that population. </jats:p></jats:sec>