Cardiac glycosides are often found within plants and can be classified as either cardenolides or bufadienolides depending on their structure. Cardenolide-containing plants are seldom eaten by livestock and of little veterinary importance. Comparatively, bufadienolide-containing plants are eaten much more often and cause a significant number of livestock mortalities. The compounds classified as bufadienolides can further be divided into two groups i.e. non-cumulative bufadienolides, which cause acute bufadienolide poisoning, and cumulative bufadienolides, that beside acute poisoning, also cause chronic intoxication. The chronic form of bufadienolide induced poisoning is a paretic condition known as krimpsiekte that mainly affect small stock. Our study objectives of this project were to confirm the neurotoxicity of the cumulative bufadienolides in vitro and compare the effects of different types of cardiac glycosides on myocardial and neuroblastoma cell lines. The in vitro cytotoxicity of the cardenolide digoxin, the non-cumulative bufadienolide 1α,2α-epoxyscillirosidine and the cumulative bufadienolide lanceotoxin B on H9c2 and Neuro-2a cells were determined using the MTT assay. The cytotoxicity of 1α,2α-epoxyscillirosidine on H9c2 cells was the greatest of the three cardiac glycosides tested. In contrast, Neuro-2a cells suffered the highest degree of cytotoxicity when exposed to lanceotoxin B. Ultrastructural changes induced by the different cardiac glycosides were examined using electron microscopy. The morphological changes induced by the cardiac glycosides was used to indicate the possible mechanism of cell death. The majority of H9c2 cells exposed to digoxin and 1α,2α-epoxyscillirosidine died via necrosis, while H9c2 cells exposed to lanceotoxin B died via apoptosis. The Neuro-2a cells exposed to digoxin showed signs of dying via apoptosis. 1α,2α-Epoxyscillirosidine caused necrosis in Neuro-2a cells, with some cells dying via the apoptotic pathway. Finally, lanceotoxin B caused many cells to exhibit the hallmark features of apoptosis, but the large autophagic vesicles present within the cytoplasm could be indicative of the involvement of autophagy in cell death.