Current evidence points to a research-practice gap in mental health. There is a specific unmet need to identify novel strategies to improve diagnostic criteria, especially when clinical manifestations overlap as in the case of bipolar (BD) and major depressive disorder (MDD). Based on the rapidly evolving notion that affective disorders are characterized by disrupted brain-body communication, current efforts of neuropsychiatric research are converging towards the identification of specific clusters of peripheral interconnected biomarkers. We argue that these can capture the complexity of the disease as they are linked to the fundamental pathophysiological mechanisms underlying BD or MDD, and can thus deliver an unbiased biosignature. Here we provide a critical viewpoint on the promises and challenges of biomarkers to identify reliable biosignatures of affective disorders. Novel methodological insight and relevant biomarkers are discussed with a main focus on immunometabolic derangements and disrupted redox balance. Major advancements are reviewed taking into consideration that an unbiased diagnosis can only derive from a deep understanding of how biological, psychological, and social factors interact ultimately affecting the clinical manifestation of affective disorders.