Depression is a leading cause of morbidity and mortality, and its treatment includes a high percentage of the medications prescribed by physicians. Available antidepressant drugs are safe and effective, but less than half of all patients attain complete remission after therapy with a single antidepressant. Others exhibit partial, refractory or intolerant responses to treatment, emphasizing the need to discover new antidepressants. The mechanisms of action of available medications are directing the field toward new research avenues. This review highlights those areas we believe will influence the field and soon lead to better treatment.