The dilemma of developing new medications rationally--as opposed to discovering them through serendipity--is to create an optimal balance between the number of mechanisms of action needed for the widest spectrum of antidepressant activity while maximizing safety and tolerability. Newer antidepressants, such as serotonin selective reuptake inhibitors (SSRIs) and venlafaxine, have a wider therapeutic index than the older tricyclic antidepressants. Fewer types of adverse effects and a reduction in the potential for pharmacodynamic interactions are the distinct benefits of all the newer targeted antidepressants, such as venlafaxine, SSRIs, and bupropion, in comparison with older drugs. However, there are important differences among the newer antidepressants in terms of effects of P450 enzymes, dose-response curves for antidepressant response and adverse effects, and dosing schedules. One of the main benefits of having a wide array of options is the evidence that there may be different forms of the illness, which respond to different mechanisms of action. More research is needed to test this concept and to develop predictors of differential responsiveness.