Major depression is a severe psychiatric syndrome with very high prevalence and - socioeconomic impact. Despite extensive research, its pathophysiology is poorly understood, yet several neurotransmitter systems and brain areas have been implicated. The pharmacological treatment of major depression is mainly based on drugs inhibiting serotonin (5-hydroxytryptamine, 5-HT) and/or noradrenaline (NA) reuptake. These drugs evoke a series of neuronal adaptive mechanisms that limit their full clinical action, making necessary for many patients the use of augmentation strategies. In spite of such strategies, many depressed patients show limited or no improvement, which worsens their quality of life and increases the risk of suicide. Several novel observations in recent years have shaken the antidepressant field, by showing that depressed patients with severe treatment resistance can rapidly experience clinical remission. Hence, deep brain stimulation (DBS) of ventral anterior cingulate cortex (Cg25) evokes rapid mood improvements in treatment-resistant patients. Likewise, single doses of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine evoke rapid and long-lasting (up to 10 days) antidepressant responses in treatment-resistant patients. On the other hand, new molecular strategies aimed at modulating the expression of certain genes show great potential in the antidepressant field. In particular, RNAi strategies have been used to evoke antidepressant-like effects in laboratory animals by knocking-down the expression of genes involved in antidepressant effects, such as the serotonin transporter (SERT) or the 5-HT1A autoreceptor. Here we review these novel strategies due to their potential impact in the identification of new targets and the further development of new antidepressant drugs.