Clinical differentiation between unipolar and bipolar depression can be a challenge. Additional diagnostic tools based on biomarkers could help resolve ambiguous cases. In this article we discuss studies from the dissertation 'Bipolar or unipolar? A brain teasing question', investigating to which extent neuroimaging could contribute to such detection.<br /> AIM: To investigate whether neuroimaging can aid in differentiating between uni- and bipolar disorder.<br /> METHOD: An analysis of the brain anatomy and functioning in medication-free uni- and bipolar participants and healthy controls using magnetic resonance imaging (MRI).<br /> RESULTS: The results indicate that there are differences regarding both brain structure and functioning when comparing unipolar and bipolar patients. The nature of these differences corresponded with the present mood state. Diagnosis could also be predicted on an individual level. However, direct implementation during clinical practice is currently not possible, in part due to the heterogeneity of the findings and the limitations inherent to MRI-research.<br /> CONCLUSION: Neuroimaging may be a promising technique for development of additional diagnostic tools to differentiate between unipolar and bipolar disorder.