The common milkweed Asclepias syriaca is widespread in North America and produces cardenolide toxins that deter herbivores by targeting the transmembrane enzyme Na+/K+-ATPase. In 1979, Nobel Laureate Tadeus Reichstein elucidated the structure of novel cardenolides isolated from A. syriaca roots and proposed structures for several other cardenolides that could not be confirmed. In this study, we investigate the cardenolide composition of A. syriaca seeds, focusing on their abundance and in vitro inhibitory potency on the sensitive porcine Na+/K+-ATPase and that of the highly resistant large milkweed bug, Oncopeltus fasciatus. We identify five previously unreported cardenolides (1-5), three of which are predominantly found in seeds, in addition to the known syrioside (6), aspecioside (7), and the 2-thiazoline ring-containing cardenolide labriformin (8). Glucopyranosyl-allomethylosyl-12-deoxy aspecioside (5) is distinguished by lack of oxidation at C-12, and compounds 2, 3, 6, and 8 contain a rare 1,4-dioxane motif. Inhibitory efficacy of the isolated cardenolides for sensitive and resistant enzymes appears to be correlated. Finally, we confirmed the structure of compound 2, originally proposed by Tadeus Reichstein, and are pleased to share his original 1979 handwritten manuscript.