Agents interfering with the reuptake of catecholamines and tryptamines are well-known drugs capable of treating serious illnesses, including depression, pain and dependence. Further therapeutic applications and use have been tested and an increase in the variety of the chemical templates has been achieved in the last few years. This review attempts to give an organic overview of molecules capable of simultaneously interfering with the reuptake of all the three major monoamine neurotransmitters (dopamine, norepinephrine/noradrenaline and serotonin).