Obesity increases the risk for liver disease, including liver cancer. The mechanisms for this association are not well understood. At the very least, obesity might function as a comorbidity factor, accentuating processes (such as microsomal enzyme induction or pro-inflammatory cytokine production) that mediate liver damage caused by alcohol, hepatotoxic drugs, or certain viral infections. However, a growing body of evidence suggests that obesity-related insulin resistance plays a fundamental role in the initiation and progression of liver damage and liver cancer by altering the viability of liver cells. Efforts to delineate the molecular mechanisms that mediate insulin’s actions on cellular apoptosis and proliferation are increasing, and should help us design more effective therapies to prevent and treat obesity-related liver diseases.