Infection with Hepatitis B virus (HBV) is the most common cause of liver disease in the world. Infection becomes chronic in up to 10 % of adults, with severe consequences on liver function, including inflammation, fibrosis, cirrhosis, and eventually hepatocellular carcinoma (HCC). HCC is a fast progressing disease causing the death of approximately one million patients annually; current treatment has very limited success, mainly due to late-stage diagnosis and poor screening methodologies. Therefore, unraveling the complex HBV-host cell interactions during progression of the disease is of crucial importance, not only to understand the mechanisms underlying carcinogenesis, but importantly, for the development of new biomarkers for prognostic and early diagnosis. This is an area of research strongly influenced by proteomic studies, which have benefited in the last decade from major technical improvements in accuracy of quantification and sensitivity, large-scale analysis of low-abundant proteins, such as those from clinical samples being now possible and widely applied. This work is a critical review of the impact of the proteomic studies on our current understanding of HBV-associated pathogenesis, diagnostics, and treatment.