Chronic hepatitis B (CHB) is one of the leading causes of morbidity and mortality worldwide. Although various drugs are available for the treatment of CHB, emergence of the hepatitis B e antigen (HBeAg)-negative mutant variant, specifically in Asia, the Middle East and southern Europe, is creating a new challenge as this variant is less responsive to available treatments. HBeAg-negative CHB rapidly progresses to cirrhosis and its related complications. This review discusses the available literature on the approved and under-trial treatment options and their respective efficacies for HBeAg-negative CHB.