Activation of Na+, K+-ATPase has previously been suggested to be the triggering signal in mitogen-induced cell activation. Using a digitalis glycoside known to be a potent polyclonal B-cell activator, this hypothesis could be tested since digitalis activates ATPase at different concentrations in various species, depending on the degree of sensitivity to the toxic effects of glycosides. Lanatoside C was found to stimulate lymphocytes from glycoside resistant species such as rat, mouse and hamster. The possible involvement of Na+, K+-ATPase was made less likely by the similarity in dose--response profile in these cells although they have been reported to display varying degrees of glycoside resistance. Furthermore, using lymphocytes from digitalis-sensitive species such as man, guinea-pig or rabbit, no mitogenicity could be recorded, strongly suggesting a lack of correlation between glycoside-induced effects on Na+, K+-ATPase and cell activation.