Neurotransmitter transporters present at the plasma membrane contribute to the clearance and recycling of neurotransmitters and have a profound impact on the extent of receptor activation during neuronal signaling. These carriers also are the primary targets for psychostimulant drugs of abuse, antidepressant medications, and drugs such as methylphenidate and amphetamines, which are used to treat attention deficit disorders in children. In recent studies we have observed that once amphetamine-like drugs enter dopamine neurons they activate multiple intracellular signaling pathways to trigger changes in the cellular trafficking of the dopamine transporter and other neuronal membrane proteins. Within the cell amphetamines activate the small GTPases, Rho and Rac1 and trigger endocytosis of the dopamine transporter (DAT) by a RhoA- and dynamin-dependent pathway. We have also found that increases in cAMP and PKA activity mediated by D1/D5 dopamine receptors or by amphetamine itself, serve as a break on DAT internalization, revealing interplay between PKA and RhoA signaling in the regulation of DAT activity. This work implies that amphetamine-like drugs not only block monoamine transport and potentiate neurotransmitter action, but also act on specific cytoplasmic targets that regulate protein trafficking and many other cellular activities. Although several key steps in the process remain to be defined, this novel intracellular mode of amphetamine action has major implications for the mechanisms of neuroplasticity and neurotoxicity associated with psychostimulant use and suggests novel drug targets for modulating the actions of amphetamines.