Neurotransmitter plasma membrane transporters do have much more to perform than simply terminating synaptic transmission and replenishing neurotransmitter pools. Findings in the past decade have evidenced their function in maintaining physiological synaptic excitability, and their actions in critical or pathological conditions, also. Conclusively these findings indicated a previously unrecognized role for neurotransmitter plasma membrane transporters in both, synaptic and nonsynaptic signaling. Major inhibitory and excitatory neurotransmitters within the brain, GABA and Glu, have long been considered to operate through independent systems (GABAergic or Gluergic), each of them characterized by its own localization, function and dedicated GABAergic or Gluergic cell phenotypes. Recent advances, however, have challenged this long-standing paradigm. Localization of GABA in Gluergic terminals and Glu in GABAergic cells were reported. Specific plasma membrane transporters for GABA and Glu are also co-localized in different brain areas. Although, their role in regulating each others signal is still far from being understood, emerging lines of evidence on interplaying GABAergic and Gluergic processes through plasma membrane transporters opens up a new avenue in the field of more specific therapeutic intervention.