High-fructose corn syrup (HFCS) is a fructose-glucose liquid sweetener alternative to sucrose (common table sugar) first introduced to the food and beverage industry in the 1970s. It is not meaningfully different in composition or metabolism from other fructose-glucose sweeteners like sucrose, honey, and fruit juice concentrates. HFCS was widely embraced by food formulators, and its use grew between the mid-1970s and mid-1990s, principally as a replacement for sucrose. This was primarily because of its sweetness comparable with that of sucrose, improved stability and functionality, and ease of use. Although HFCS use today is nearly equivalent to sucrose use in the United States, we live in a decidedly sucrose-sweetened world: >90% of the nutritive sweetener used worldwide is sucrose. Here I review the history, composition, availability, and characteristics of HFCS in a factual manner to clarify common misunderstandings that have been a source of confusion to health professionals and the general public alike. In particular, I evaluate the strength of the popular hypothesis that HFCS is uniquely responsible for obesity. Although examples of pure fructose causing metabolic upset at high concentrations abound, especially when fed as the sole carbohydrate source, there is no evidence that the common fructose-glucose sweeteners do the same. Thus, studies using extreme carbohydrate diets may be useful for probing biochemical pathways, but they have no relevance to the human diet or to current consumption. I conclude that the HFCS-obesity hypothesis is supported neither in the United States nor worldwide.