Depression is a severe neuropsychiatric disorder affecting approximately 10% of the world population. Despite this, the molecular mechanisms underlying the disorder are still not understood. Novel technologies such as proteomic-based platforms are beginning to offer new insights into this devastating illness, beyond those provided by the standard targeted methodologies. Here, we will show the potential of proteome analyses as a tool to elucidate the pathophysiological mechanisms of depression as well as the discovery of potential diagnostic, therapeutic and disease course biomarkers.Depression, unipolar depression, clinical depression or major depressive disorder (MDD) is a brain disorder which affects around 10% of world population [76]. It is characterized by low mood, low self-esteem, inappropriate guilt, thoughts of death and suicide, diminished concentration, loss of interest or pleasure in normally enjoyable activities, and disturbance of sleep and appetite. In the United States, approximately 3% of depressed patients commit suicide and around 60% of people who commit suicide have MDD or another mood disorder (NIH). MDD is a leading cause of global disability and a risk factor for non-compliance with medical treatment [11].MDD appears to be a multifactorial disease arising from genetic or metabolic predisposition in conjunction with environmental factors such as stressful life events and other stressors. Even though there is no anatomical hallmark, the risk of MDD may be due to significant variations in responsiveness of neural circuits and can be affected by other factors such as addiction or alterations in the dopaminergic system and the molecular mechanisms of memory [5].Neuropathological studies have shown volume deficits, decreased neuronal size and glial pathology as well as decreased expression of synaptic markers, particularly in the anterior cingulate, orbitofrontal and dorsolateral prefrontal cortices [26]. Hippocampal volume reductions have been demonstrated by magnetic resonance imaging (MRI) [53] and may be linked to the effects of stress, hypercortisolaemia and hypothalamic-pituitary-adrenal (HPA) axis dysfunction, although evidence of cellular correlates for such effects is lacking [26]. Hippocampal neurogenesis has also been proposed as an underlying factor in the biology of MDD, mainly based on animal model studies and the effects of antidepressant medication [13]. For the last three decades, the main line of investigation into the neurobiology of MDD has been focused on changes in the monoamine neurotransmitters serotonin and norepinephrine, based on the known mechanisms of action of drugs with antidepressant activity. However, the relationship between low neurotransmitter levels and symptomatology is not simple and may be dependent on genetic background [1].D. Martins-de-Souza and L. W. Harris contributed equally to this work.