Many insects are highly resistant to plant toxins, such as the cardiac glycoside ouabain. How can the epithelia that must handle such toxins, also be refractory to them? In Drosophila, the Malpighian (renal) tubule contains large amounts of Na(+),K(+) ATPase that is known biochemically to be exquisitely sensitive to ouabain, yet the intact tissue is almost unaffected by even extraordinary concentrations. The explanation is that the tubules are protected by an active ouabain transport system, colocated with the Na(+),K(+) ATPase, thus preventing ouabain from reaching inhibitory concentrations within the basolateral infoldings of principal cells. These data show that the Na(+),K(+) ATPase, previously thought to be unimportant, may be as vital in insect tissues as in vertebrates, but can be cryptic to conventional pharmacology.