Seawater acclimation in killifish, Fundulus heteroclitus, is mediated in part by a rapid (1h) translocation of CFTR Cl(-) channels from an intracellular pool to the plasma membrane in gill and increased CFTR-mediated Cl(-) secretion. This effect is mediated by serum and glucocorticoid-inducible kinase 1 (SGK1), which is stimulated by plasma hypertonicity rather than cortisol. Since arsenic exposure prevents acclimation to seawater by decreasing CFTR protein levels we tested the hypothesis that arsenic (as sodium arsenite) blocks acclimation to seawater by down regulating SGK1 expression. Freshwater adapted killifish were exposed to arsenic (48h) and transferred to seawater containing arsenic, and SGK and CFTR expression were measured. Arsenic reduced the seawater induced increase in SGK1 mRNA and protein abundance, and reduced both the total amount of CFTR and the amount of CFTR in the plasma membrane. The decrease in membrane CFTR reduced Cl(-) secretion. Arsenic also increased the amount of ubiquitinated CFTR and its degradation by the lysosome. Thus, we propose a model whereby arsenic reduces the ability of killifish to acclimate to seawater by blocking the seawater induced increase in SGK1, which results in increased ubiquitination and degradation of CFTR.