Biogenic amine transporters for serotonin, norepinephrine and dopamine (SERT, NET and DAT respectively), are the key players terminating transmission of these amines in the central nervous system by their high-affinity uptake. They are also major targets for many antidepressant drugs. Interestingly however, drugs targeted to a specific transporter do not appear to be as clinically efficacious as those that block two or all three of these transporters. A growing body of literature, reviewed here, supports the idea that promiscuity among these transporters (the uptake of multiple amines in addition to their "native" transmitter) may account for improved therapeutic effects of dual and triple uptake blockers. However, even these drugs do not provide effective treatment outcomes for all individuals. An emerging literature suggests that "non-traditional" transporters such as organic cation transporters (OCT) and the plasma membrane monoamine transporter (PMAT) may contribute to the less than hoped for efficacy of currently prescribed uptake inhibitors. OCT and PMAT are capable of clearing biogenic amines from extracellular fluid and may serve to buffer the effects of frontline antidepressants, such as selective serotonin reuptake inhibitors. In addition, polymorphisms that occur in the genes encoding the transporters can lead to variation in transporter expression and function (e.g. the serotonin transporter linked polymorphic region; 5-HTTLPR) and can have profound effects on treatment outcome. This may be accounted for, in part, by compensatory adaptations in other transporters. This review synthesizes the existing literature, focusing on serotonin to illustrate and revive a model for the rationale design of improved antidepressants.