Chloride ions contribute to the osmotic pressure gradient distinguishing the intracellular fluid (ICF) from the extracellular fluid (ECF). They counterbalance positively charged ions in the ECF and ensure its electrochemical stability. The renal system's process of chloride absorption and release generally mirrors that of sodium ions.

Conditions such as hypochloremia can arise from insufficient chloride reabsorption by the kidneys, often compounded by extended bouts of diarrhea, vomiting, or conditions that induce metabolic acidosis. On the flip side, hyperchloremia refers to an atypically high concentration of chloride in the blood, possibly triggered by factors like dehydration, excessive salt intake, ingestion of ocean water, aspirin overdose, or diseases like cystic fibrosis. For individuals with cystic fibrosis, a diagnostic indicator is a notably high chloride concentration in their sweat—often two to five times the normal level.

As a key regulator of the body's pH balance, bicarbonate is the second most prevalent blood anion. It is part of the buffer system that will be elaborated upon in a separate segment.

Bicarbonate is synthesized in a reaction that begins with carbon dioxide (CO2) and water, byproducts of the body's aerobic metabolism. Due to the limited solubility of CO2 in bodily fluids, it is predominantly converted into bicarbonate ions inside red blood cells. This conversion is influenced by the relative concentrations of its substrates and products. High metabolic activity within certain tissues generates considerable amounts of carbon dioxide, which is subsequently transformed into bicarbonate in the cytoplasm of red blood cells thanks to the enzyme carbonic anhydrase. Transported via the bloodstream and reaching the lungs, bicarbonate then reverts back to CO2—a waste product expelled during exhalation.