Chronic HCV infection is a global health problem that affects >184 million people worldwide. HCV is associated with several hepatic and extrahepatic disorders, including several malignancies. The burden of HCV-related disorders is influenced by the number of new and existing cases, number of existing cases and the natural history of the infection. The natural history of HCV is affected by several demographic, virological, clinical and lifestyle factors. Major variations exist in the burden of HCV among different populations and geographical regions, as well as over time. With the advent of new and efficacious antiviral treatments, it is important to learn the determinants of HCV burden to design appropriate strategies for detection, prognostication and treatment. Furthermore, with the expected growth of patients cured of HCV, it is essential to learn about the possible change in natural history and burden of disease in these patients. In this Review, we will discuss the global epidemiology and burden of HCV and its complications, as well as the natural history and clinical course of chronic and cured HCV infection.