The development of the radioimmunoassay for digoxin by Smith and coworkers in 1969 was a landmark in digitalis therapy. Since then, the complex pharmacokinetics of digoxin have been defined. As a result, the incidence of digitalis toxicity has markedly decreased. To use the digoxin assay properly, however, the relation of this pharmacokinetic parameter to digoxin pharmacodynamics must be known and the limitations of the assay itself understood. Systolic time intervals (STI) are uniquely useful to quantitate the inotropic effect of digitalis preparations. This technique can demonstrate the onset and magnitude of the inotropic effect for both oral and intravenous digitalis administration. By defining the mathematical relation between STI and simultaneous serum digoxin concentrations following intravenous administration of 1 mg digoxin, computer simulations can be made of the effect of dosing changes on blood and tissue concentrations. The serum digoxin assay has technical problems relating to quality control, interference by metabolites, and cross-reactions with endogenous digitalis-like substances. Further, a standard time for measurement following dosing has not been established. Physical activity can significantly alter the serum digoxin concentrations by increasing skeletal muscle binding. Numerous drugs can interfere with digoxin absorption or elimination. Using the serum digoxin assay is the only way to assess these interactions. Computer surveillance (ideally with physician or pharmacist interaction) has been used to monitor digitalis but has not yet gained widespread acceptance. This is clearly a method in need of further testing.