The blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) represent major control checkpoints protecting the CNS, by exerting selective control over the movement of organic cations and anions into and out of the CNS compartment. In addition, multiple CNS cell types, e.g., astrocytes, ependymal cells, microglia, contribute to processes that maintain the status quo of the CNS milieu. To fulfill their roles, these barriers and cell types express a multitude of transporter proteins from dozens of different transporter families. Fundamental advances over the past few decades in our knowledge of transporter substrates, expression profiles, and consequences of loss of function are beginning to change basic theories regarding the contribution of various cell types and clearance networks to coordinated neuronal signaling, complex organismal behaviors, and overall CNS homeostasis. In particular, transporters belonging to the Solute Carrier (SLC) superfamily are emerging as major contributors, including the SLC22 organic cation/anion/zwitterion family of transporters (includes OCT1-3 and OCTN1-3), the SLC29 facilitative nucleoside family of transporters (includes PMAT), and the SLC47 multidrug and toxin extrusion family of transporters (includes MATE1-2). These transporters are known to interact with neurotransmitters, antidepressant and anxiolytic agents, and drugs of abuse. Clarifying their contributions to the underlying mechanisms regulating CNS permeation and clearance, as well as the health status of astrocyte, microglial and neuronal cell populations, will drive new levels of understanding as to maintenance of the CNS milieu and approaches to new therapeutics and therapeutic strategies in the treatment of CNS disorders. This chapter highlights organic cation transporters belonging to the SLC superfamily known to be expressed in the CNS, providing an overview of their identification, mechanism of action, CNS expression profile, interaction with neurotransmitters and antidepressant/antipsychotic drugs, and results from behavioral studies conducted in loss of function models (knockout/knockdown).