Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Interestingly, the great majority of individuals affected by the tumor have underlying liver disease, therefore narrowing the population to be screened. Still, however, there is a clear lack of blood biomarkers, and surveillance in those at risk is performed by frequent imaging of the liver. A variety of multinational collaborations are currently invested in finding biomarkers for HCC based on liver-produced proteins. A new approach with assessment of peripheral proteins might be necessary for the successful early detection of this malignancy.