SLC6 transporters, which include transporters for gamma-aminobutyric acid (GABA), norepinephrine, dopamine, serotonin, glycine, taurine, L-proline, creatine, betaine, and neutral cationic amino acids, require Na+ and Cl- for their function, and this review covers the interaction between transporters of this family with Na+ and Cl- from a structure-function standpoint. Because detailed structure-function information regarding ion interactions with SLC6 transporters is limited, we cover other proteins cotransporting Na+ or Cl- with substrate (SLClA2, PutP, SLC5A1, melB), or ion binding to proteins in general (rhodanese, ATPase, LacY, thermolysine, angiotensin-converting enzyme, halorhodopsin, CFTR). Residues can be involved in directly binding Na+ or Cl-, in coupling ion binding to conformational changes in transporter, in coupling Na+ or Cl- movement to transport, or in conferring ion selectivity. Coordination of ions can involve a number of residues, and portions of the substrate and coupling ion binding sites can be distal in space in the tertiary structure of the transporter, with other portions that are close in space thought to be crucial for the coupling process. The reactivity with methanethiosulfonate reagents of cysteines placed in strategic positions in the transporter provides a readout for conformational changes upon ion or substrate binding. More work is needed to establish the relationships between ion interactions and oligomerization of SLC6 transporters.