Only one-third of patients undergoing monotherapy with an antidepressant achieve remission of their depressive symptoms and gain functional recovery. Therefore, further exploration of antidepressant mechanisms of action is important in order to facilitate the development of antidepressants with new modes of action. Preclinical and clinical studies have demonstrated that major depression is associated with impaired inflammatory responses and deficient neuroprotection. In this regard, we propose that the second-generation tetracycline "minocycline" may hold a potential as a new treatment for major depression. Emerging findings in animal and human studies of minocycline reveal that it has antidepressant-like neuroprotective and anti-inflammatory actions, and minocycline has been shown to perform as an antidepressant in an accepted animal model (forced swimming test). Anecdotal evidence supports minocycline's efficacy for augmentation of antidepressants in major depressive disorder. The following review describes the evidence supporting the consideration of minocycline as a potential antidepressant. We suggest that minocycline may be particularly helpful in patients with depression and comorbid cognitive impairment, as well as depression associated with organic brain disease. We also describe the antinociceptive effect of minocycline and propose a role for minocycline in the treatment of patients with major depression and prominent somatic discomfort and somatoform spectrum disorders. The lack of clinical studies of minocycline for depression is noted. Further studies of the potential therapeutic mechanism of minocycline and its therapeutic implications for major depression are warranted, and may substantially contribute to the development of newer and more effective antidepressants.