Although unipolar depression and bipolar depression are considered distinct entities both by clinicians and researchers, it is not clear whether a pathophysiological distinction, which is the bridge between etiology and treatment, exists between these two conditions. The objective of this paper was to systematically review the studies that examined the biological differences between unipolar and bipolar depression. Using computerized Medline and manual searches, we located and reviewed studies that directly compared patients with unipolar depression with bipolar depressed patients on at least one biological variable. The results showed that patients with bipolar depression had lower levels of urinary NE and its metabolites and lower platelet MAO activity, and higher platelet free and stimulated intracellular calcium levels compared with unipolar depressed patients, but none of the variables examined appeared to differentiate the two groups consistently. We discuss some of the methodological flaws that might have contributed to this, and suggest that further studies should control for such confounding variables.