There is evidence that the serotonin norepinephrine reuptake inhibitors (SNRIs) venlafaxine, milnacipran, and duloxetine, have probable superior antidepressant activity to most selective serotonin reuptake inhibitors (SSRIs), especially in more severe depression. Some patients, however, respond better than others to SNRIs. Several factors influencing response to milnacipran have been recently studied. The presence of certain polymorphisms related to noradrenergic neurotransmission has been shown to be related to different degrees or rapidity of response to milnacipran. In addition, patients with low pretreatment levels of plasma 3-methoxy-4-hydroxyphenylglycol have a better response to milnacipran. These recent genomic and neurochemical data confirm that milnacipran, in contrast to SSRIs and venlafaxine, has an impact on the noradrenergic system. Differences in metabolism determined by genetic variables in cytochrome P450 (CYP) 2D6 activity are a major determinant of venlafaxine levels to such an extent that genetically determined decreases in CYP 2D6 activity have been associated increased adverse effects. Milnacipran, which is not metabolized by the enzymes of the CYP system is not influenced by polymorphism of these enzymes. These preliminary data suggest that a patient's biochemical and pharmacogenetic characteristics may be useful in the future to help clinicians chose the most  effective antidepressant medication.