Fructose consumption has dramatically increased in the last 30 years. The principal form has been in the form of high-fructose corn syrup found in soft drinks and processed food. The effect of excessive fructose consumption on human health is only beginning to be understood. Fructose has been confirmed to induce several obesity-related complications associated with the metabolic syndrome. Here we present an overview of fructose metabolism and how it contrasts with that of glucose. In addition, we examine how excessive fructose consumption can affect de novo lipogenesis, insulin resistance, inflammation, and reactive oxygen species production. Fructose can also induce a change in the gut permeability and promote the release of inflammatory factors to the liver, which has potential implications in increasing hepatic inflammation. Moreover, fructose has been associated with colon, pancreas, and liver cancers, and we shall discuss the evidence for these observations. Taken together, data suggest that sustained fructose consumption should be curtailed as it is detrimental to long-term human health.