Hepatitis C virus (HCV) is a major cause of chronic liver disease worldwide. The severity of disease varies widely from mild illness to cirrhosis and hepatocellular carcinoma. The progression of liver fibrosis in HCV patients determines the prognosis and, thus, the need for and urgency of therapy. In addition to viral and environmental behavioral factors, host genetic diversity is believed to contribute to the spectrum of clinical outcomes of patients chronically infected with HCV. The sequencing of the human genome together with the development of high-throughput technologies has provided opportunities to distinguish discrete subsets of HCV disease and predict the disease outcome or the response to therapy. This article reviews genetic, genomic, and proteomic aspects associated with the natural history of HCV infection (i.e., viral clearance, fibrosis progression) and the response to therapy.