The effects of intracellular acidification, osmotic shrinkage and beta-adrenergic stimulation on sodium transport across the membrane of lamprey (Lampetra fluviatilis) erythrocytes were investigated. Unidirectional ouabain-insensitive sodium flux, measured using radioactive Na-22, was increased markedly by intracellular acidification, to a lesser extent by osmotic shrinkage and only modestly by beta-adrenergic stimulation. Na+/H+ exchange was activated in all of these cases. However, net sodium influx (and cell swelling caused by the influx of osmotically obliged water) was seen only in cells subjected to intracellular acidification. In contrast, practically no changes in red cell pH or in water or ion (Na+, K+ and Cl-) contents were seen after osmotic shrinkage or beta-adrenergic stimulation. Calculations of the [Na+](o)/[Na+](i) and [H+](o)/[H+](i) ratios across the erythrocyte membrane suggest that the virtual lack of net sodium movements in osmotically shrunken erythrocytes is due to the absence of a driving force for net transport of these ions via the Na+/H+ exchange pathway. It also appears that, in physiological conditions, the increase in the activity of the Na+/H+ exchanger by beta-adrenergic stimulation is too small to mediate detectable net sodium transport.