Abstract: Digitoxin is a widely used cardiac glycoside for treatment of congestive heart failure. Its good antitumor activity has also drawn increasing attention. Great efforts have been made toward the total synthesis as well as the structural modification and structure-activity relationship (SAR) studies on digitoxin aiming to improve the activity and decrease the toxicity. This review summarizes progress in total synthesis and structural modification on the sugar moiety of digitoxin over the last ten years as well as its structure-activity relationships, so as to provide reference for total synthesis of cardiac glycoside and its structural modification as well as the discovery of new antitumor cardiac glycosidic drugs with low toxicity and high efficiency.