In a treatment-naive patient with chronic hepatitis B, a personalized approach allows treatment efficacy to be optimized. Firstly, the selection of good candidates for therapy is crucial. Patients with chronic active hepatitis B--with relatively low levels of HBV DNA replication (<10(9) copies/ml) and relatively high alanine aminotransferase (ALT) levels--are good candidates for therapy. By contrast, patients with chronic hepatitis B in the immunotolerance phase, who have high levels of HBV DNA and persistently normal ALT levels, as well as inactive hepatitis B surface antigen (HBsAg) carriers with low HBV DNA and normal ALT levels do not have an indication for therapy as they are poor responders. Secondly, the characteristics of the patient (for example, gender, age, immune status, general health status and comorbidities), the characteristics of the liver disease (for example, presence of cirrhosis and liver function) and the characteristics of the virus (for example, genotype) are important when assessing the chance of success and when choosing the best therapeutic strategy (nucleoside/nucleotide analogue or interferon). Thirdly, during therapy, the antiviral effect--assessed by decrease in HBV DNA level--allows an individualized response-guided approach. In addition, quantification of HBsAg after 3-6 months of interferon therapy appears to be a good predictor of sustained virological response after treatment and HBsAg clearance. Continuing interferon therapy until week 48 is justified in patients with a significant decrease in HBsAg. Ongoing and future studies will provide useful information regarding prolonging interferon therapy beyond 48 weeks in some patients in order to increase efficacy, and also regarding the role of combination therapy with interferon and potent nucleoside/nucleotide analogues, such as entecavir or tenofovir disoproxil fumarate.