Antidepressant drugs have been available for more than 40 years. However, essentially all drugs currently available share the common mechanism of modulating the synaptic transmission of the monoamines serotonin (5-HT), noradrenaline (NE), or dopamine (DA). The mechanisms of action of available drugs include the enhancing the synaptic availability of the monoamines via blockade of the high-affinity transporter proteins for these transmitters or α-1 receptors, or antagonism of 5-HT receptors. Although the available medications are often effective, treatment resistance is common and many patients discontinue prematurely because of side effect problems. More recently, evidence has accumulated suggesting that antidepressants may have effects beyond the postsynaptic receptors. Enhancement or inhibition of mRNA expression for a number of polypeptides have been demonstrated. These proposed ultimate effects of antidepressant agents, such as increasing the expression of glucocorticoid receptors and brain derived neurotrophic factor or inhibition of NMDA receptor subunit and corticotropin releasing hormone (CRH) expression, relate to possible new therapeutic targets for antidepressant development. This paper will present data supporting potential new drug targets: antagonists for CRH, NMDA, neurokinins and agonists for neuropeptide Y1 receptors, as well as reviewing recent relevant patents. The problems with establishing new antidepressant agents will also be discussed.