Despite recent breakthroughs in the treatment for both early and advanced hepatocellular carcinoma, the development of markers for prognostication and treatment monitoring remains to be explored. Serum alpha-fetoprotein has been frequently measured at diagnosis and serially during treatment by clinicians for decades, with an aim for prognostication of disease and monitoring of treatment response. In this review, the evidence regarding the prognostic value of serum alpha-fetoprotein and the value of serial alpha-fetoprotein in the monitoring of treatment efficacy will be discussed, with emphasis on recent data.