The oleander is an attractive and hardy shrub that thrives in tropical and subtropical regions. The common pink oleander, Nerium oleander, and the yellow oleander, Thevetia peruviana, are the principle oleander representatives of the family Apocynaceae. Oleanders contain within their tissues cardenolides that are capable of exerting positive inotropic effects on the hearts of animals and humans. The cardiotonic properties of oleanders have been exploited therapeutically and as an instrument of suicide since antiquity. The basis for the physiological action of the oleander cardenolides is similar to that of the classic digitalis glycosides, i.e. inhibition of plasmalemma Na+,K+ ATPase. Differences in toxicity and extracardiac effects exist between the oleander and digitalis cardenolides, however. Toxic exposures of humans and wildlife to oleander cardenolides occur with regularity throughout geographic regions where these plants grow. The human mortality associated with oleander ingestion is generally very low, even in cases of intentional consumption (suicide attempts). Experimental animal models have been successfully utilized to evaluate various treatment protocols designed to manage toxic oleander exposures. The data reviewed here indicate that small children and domestic livestock are at increased risk of oleander poisoning. Both experimental and established therapeutic measures involved in detoxification are discussed.