Solute carrier 6 family members comprise of neurotransmitter sodium symporters that are the transporters primarily involved in the reuptake of released neurotransmitters from the synaptic space. The family includes structurally related transporters involved in biogenic amine and amino acid neurotransmitter uptake and is a well-known therapeutic target for several classes of inhibitors for the treatment of ailments ranging from depression, pain, addiction, seizures and anxiety. Inhibition of NSS transporters can work either through competitive inhibition or through allosteric inhibition at diverse sites that target multiple conformational states of the transporters. This chapter explores the diverse inhibition strategies observed with numerous inhibitors that target this class of transporters and potential for improvements in inhibition strategies.