Evidence on the link between the immune system and Major Depressive Disorder (MDD) has led to explore antidepressant properties of anti-inflammatory drugs. Among these, minocycline has been identified as a potential novel treatment for MDD, in particular for treatment-resistant depression. The aim of the current paper is to review current pre-clinical and clinical evidence on the antidepressant efficacy of minocycline. The review includes considerations on the role of both peripheral and central inflammation in the response to minocycline and comparisons of minocycline efficacy across different psychiatric disorders (i.e., unipolar depression, bipolar depression, and schizophrenia).