HBsAg was the Nobel prize discovery that identified HBV about 40 years ago; to this day HBsAg remains the hallmark of overt HBV infection. HBsAg synthesis during the HBV viral life cycle is complex, and typically occurs at the endoplasmic reticulum. The envelope open reading frame (ORF) contains pre-surface 1 (preS1), pre-surface 2 (preS2), and ORF-S domains and envelope proteins are generated from two HBV messenger ribonucleic acid (mRNA) transcripts, with subsequent translation resulting in small (ORF-S), medium (pres2 + ORF-S) and large surface envelope proteins (preS1 + preS2 + ORF-S). These are also known as large (L), medium (M) and small (S) surface proteins, respectively. However, HBsAg production far exceeds that required for virion assembly, and excess surface envelope proteins are secreted as non infectious filamentous or spherical sub-viral particles, which exceed virions by a variable factor of 102-105 and can accumulate up to concentrations of several hundred micrograms per milliliter of serum. These data suggested that sAg mainly derive from sub-viral particles, and the decline of serum HBsAg means reduction of covalently closed circular DNA (cccDNA) transcription and mRNA translation but not HBV replication. Recently, several studies suggest a new potential role of quantitative serum HBsAg in the prediction of virological response to antiviral therapy, at least in pegylated interferon (Peg-IFN) treated patients. In natural history of chronic HBV infection, HBsAg levels differ significantly during the 4 phases of HBV infection and decline progressively from immune tolerance (IT) (5 log IU/ml) to low replication (LC) (3 log IU/ml), while HBsAg/HBV-DNA ratios are significantly higher in LC as compared to all the others patients. These data suggested that the quantitative HBsAg may be a promising prognostic marker during the natural history of HBV-infection and during antiviral therapy. Thus, the loss of HBsAg and the development of anti-HBs antibodies (HBsAg-seroconversion) is the ultimate goal of anti-HBV therapy.