International treatment guidelines for hepatitis B emphasize alanine aminotransferase (ALT) and serum HBV DNA thresholds, but strict adherence to these markers might lead to missed opportunities in some patients with acquisition in early life. Clinical trials have used improvement in liver histology, rate of hepatitis B e antigen seroconversion and sustained HBV DNA suppression as primary end points. These are potentially short-term end points because HBV infection can not be eradicated and delayed relapses might occur. The closest end point to a clinical cure of disease is the loss of hepatitis B surface antigen (HBsAg). The ability of interferon to stimulate the immune response of the host might explain the higher rate of early HBsAg clearance when compared with nucleoside analogues. Early studies suggest that combination therapy with interferon and long-term treatment with nucleoside analogues might lead to an even higher rate of HBsAg seroconversion. Measuring HBsAg concentration during therapy might provide an early indication that a durable virological response, including HBsAg clearance, is likely to occur. Thus far, this has been best studied using interferon. The relationship of this phenomenon to viral genotype will be discussed. There is a need for more flexible on-treatment criteria for hepatitis B. HBsAg clearance remains the best therapeutic end point, but is not readily achievable with current treatments. Future treatment paradigms should take into account the duration as well as the extent of viraemia, place less reliance on the ALT level to indicate the extent of liver injury and consider the possibility that maintenance therapy can prevent liver disease complications.