A major function of the blood brain barrier (BBB) and blood cerebrospinal fluid barrier (BCSFB) is to exert selective control
over the flux of organic cations and anions into and out of the CNS compartment. These barriers are dynamic tissues that accomplish this
task by expressing dozens of transporter proteins representing numerous transporter families. One such family, belonging to the Solute
Carrier (SLC) superfamily, is the organic cation/anion/zwitterion (SLC22) family of transporters, which includes the organic cation
transporters (OCTs/OCTNs) and organic anion transporters (OATs). SLC22 transporters interact with a broad range of compounds that
include drugs of abuse, environmental toxins/toxicants, opioid analgesics, antidepressant and anxiolytic agents and neurotransmitters and
their metabolites. Defining the transport mechanisms controlling the CNS penetration, disposition and clearance of such compounds is
fundamental to advancing our understanding of the underlying mechanisms that regulate CNS homeostasis and impact neuronal health.
Such information might help direct efforts to improve the efficacy and clinical outcomes of current and future therapeutic agents used in
the treatment of CNS disorders. This review focuses on highlighting the identification of the SLC22 transporter family, current knowledge
of OCT and OAT expression within the CNS (including brain capillaries, choroid plexus and brain regions relevant to monoaminergic
neuronal signaling), and recent data regarding behavioral changes related to mood and anxiety disorders and altered responses to
stimulants and antidepressants in SLC22 loss of functions models (knockout/knockdown). In vitro and in vivo evidence of SLC22 localization
and transport characteristics within the CNS compartment are summarized.