Acidosis is associated with poor outcome in critical illness. However, acidosis - both hypercapnic and metabolic - has direct effects that can limit tissue injury induced by many causes. There is also a clear potential for off-target harm with acute exposure (for example, raised intracranial pressure, pulmonary hypertension), and with exposure for prolonged periods (for example, increased risk of infection) or at high doses. Ongoing comprehensive determination of molecular, cellular and physiologic impact across a range of representative pathologies will allow us to understand better the risks and benefits of hypercapnia and acidosis during critical illness.