High fructose corn syrup (HFCS) is a liquid sweetener of glucose-fructose monomer mixture, commonly known as replacement for sucrose (table sugar). HFCS was first applied to food companies in the early 1970s ever since there was a huge increase of its use worldwide, especially in beverage and processed food. While the metabolic and nutritional characteristics of HFCS have been widely studied, only recently has the role of HFCS in metabolic syndrome and other health issues emerged. Studies in many laboratories worldwide have built the evidence that excessive consumption of HFCS plays a crucial role in insulin resistance, dyslipidemia, obesity, hypertension, and kidney disease. This manuscript reviews the history, manufacturing process, and nutritional and metabolic traits of HFCS and describes its involvement in the pathogenesis of metabolic syndromes and obesity.