Wolfberry is a traditional “affinal drug and diet” in Chinese and Eastern cultures, which is thought to nourish the liver, kidneys, and eyes for over one thousand years. Modern scientific studies have proved that wolfberry and its derivatives could prevent and treat a variety of diseases of the liver, gut, retina, neuron, and kidneys. However, due to its nature of mixture of a large number of constituents, it is quite difficult to delineate the major effective constituent and therapeutic mechanism responsible for those beneficial effects. This review will briefly introduce the recent progress of the botanical characteristic, metabolism, structural classification and disease therapy of the major constituent—zeaxanthin dipalmitate (ZD)—and its derivatives from wolfberry carotenoids. In most published literatures, the health-promoting properties of wolfberry were investigated from Lycium barbarum polysaccharides, which were mixtures of mostly carbohydrates and a small part of pigments/proteins. Recently, we isolated wolfberry into 5 parts, including polysaccharides, lycibarbars- permidines, polyphenols, phenylpropionoyl phenylethylamine, and carotenoids. By using several disease screening models, we found that the carotenoid extract of wolfberry could, at least partly, represent its disease prevention and therapy functions. Since ZD was shown to be the major constituent (~81.5%–87.5%) in total carotenoids of wolfberry, we considered that ZD could be a representative constituent of wolfberry. Thus, we firstly investigated the molecular mechanisms for the storage, synthesis, and degradation of ZD and other carotenoids during Lycium barbarum growth. Then we isolated and characterized all 15 carotenoid constituents from wolfberry. It was found that free carotenoids were the main pigments of immature wolfberry while esterified carotenoids (e.g. ZD) consisted most of the pigment materials in mature fruit. Thirdly, we reviewed the protective effects and possible mechanisms of ZD and its derivatives on liver diseases (e.g. acute liver failure, alcoholic liver injury, non-alcoholic fatty liver disease and viral hepatitis), stem cell injury and transplantation, cardiovascular disorders, eye diseases, and other digestive system syndromes, including tumors. In addition, possible future research directions and contents of ZD will also be discussed, such as (i) can ZD represent most of the beneficial functions of wolfberry, or synergistic promoting effects are existed between ZD and other distinct constituents from wolfberry (e.g. lycibarbarspermidines or polyphenols)? (ii) what is the optimal consumption dosage of ZD in daily life and is there any adverse effect of this kind of carotenoids? (iii) what is the exact metabolic pathways and tissue distribution after ZD consumption? We strongly believe that delineation of those questions will definitive promote basic study, clinical application, and industrial development of wolfberry in the world.