The cardiac steroids (or glycosides) are a heterogeneous group of compounds that have been well recognized for both their clinical benefit and inherent toxicity. This review will primarily focus on digoxin because of its widespread clinical use, although the other cardiac steroids will be discussed in less detail. The cardiac steroids have a narrow therapeutic index and remain a significant source of toxicity, with nearly 5000 human exposures reported to the American Association of Poison Control Centers in 2002. Digoxin reversibly binds to the α subunit of the Na+ -K+ ATPase pump and completely inhibits its enzymatic and transport functions. The cumulative effect on cardiac tissue is dependent on the number of Na+ -K+ ATPase pump sites that are occupied by cardiac steroid molecules. It is important to recall the pharmacokinetics of digoxin in that serum digoxin levels drawn prior to tissue distribution (<6 hours) do not accurately reflect acute toxicity. Signs and symptoms of toxicity vary between acute and chronic intoxications. A systematic approach guided by clinical symptoms with early administration of immunotherapy can lead to a significant reduction of morbidity and mortality in digoxin-poisoned patients.