The most common mutation in cystic fibrosis, ΔF508, results in a cystic fibrosis transmembrane conductance regulator (CFTR) protein that is retained in the endoplasmic reticulum (ER). Retention is dependent upon chaperone proteins, many of which require Ca⁺⁺ for optimal activity. Interfering with chaperone activity by depleting ER Ca⁺⁺ stores might allow functional ΔF508-CFTR to reach the cell surface. We exposed several cystic fibrosis cell lines to the ER Ca⁺⁺ pump inhibitor thapsigargin and evaluated surface expression of ΔF508-CFTR. Treatment released ER-retained ΔF508-CFTR to the plasma membrane, where it functioned effectively as a Cl⁻ channel. Treatment with aerosolized calcium-pump inhibitors reversed the nasal epithelial potential defect observed in a mouse model of ΔF508-CFTR expression. Thus, ER calcium-pump inhibitors represent a potential target for correcting the cystic fibrosis defect.