Clinical progression of chronic hepatitis C depends on several cofactors, which also have a negative affect on the rate of response to interferon-alpha-based therapy. Given the current worldwide prevalence of the metabolic syndrome, the impact of obesity and insulin resistance, and of their histopathological correlate, hepatic steatosis, on the natural history and management of chronic hepatitis C is undoubtedly very important. We will review some of the current knowledge on the clinical consequences of overweight/obesity, steatosis and insulin resistance on chronic hepatitis C, and discuss how this issue may be dealt with in clinical practice.