Interferon-α and ribavirin combination therapy has been the current choice for treating chronic hepatitis C (CHC) patients. The treatment takes 6 to 12 months but the overall sustained response rate is only around 50% and often brings significant adverse effects to some patients. The treatment outcome has been shown to be associated with various viral factors, such as viral loads before and during treatment and, most importantly, viral genotypes and quasispecies. Host factors that may affect drug response include age, gender, ethnicity, HLA alleles and stage of liver fibrosis. Recent studies have further indicated an association between patients genotypes and their treatment efficacy. In this review article, we evaluate and summarize factors that may contribute to the treatment outcome of CHC. The content is divided into four categories: 1. viral factors: viral load, viral genotype and early viral response; 2. general host factors: gender, age, treatment period/dosage and kinds of IFN; 3. host genetic polymorphisms, particularly single nucleotide polymorphism (SNP) association studies; and 4. gene expression profiles in hepatitis C liver tissues. In summary, recent advances in pharmacogenomics have demonstrated the potential applications of genetic polymorphisms and expression patterns in determining treatment responsiveness in chronic hepatitis C. By combining both human and viral genotypes and their expression, it becomes plausible to satisfactorily assess the clinical outcomes prior to interferon combination treatment for CHC patients.