Hepatocellular carcinoma (HCC) represents approximately 85 to 90% of all primary liver cancers (PLC) and every year, more than 560,000 people are diagnosed as affected by this cancer. The identification of risk factors for HCC prompted the creation of screening and surveillance programs in patients affected by chronic liver diseases with the aim of detecting HCC nodules as soon as possible and provide effective and hopefully curative therapy A correct diagnosis is of paramount importance for the surveillance program as well as for the choice of the appropriate therapy. Both in the diagnosis of small HCC and in the choice of the therapy for locally advanced HCC the diagnosis must be certain. Improvements of the radiological imagine techniques have surely enhanced both early diagnosis and tumor staging, allowing a reasonably accurate diagnosis, but cannot provide the certainty that in clinical practice is essential for an adequate workout. Therefore, the histopatological definition of the tumor is imperative both for an appropriate therapy and for an accurate prognostic evaluation.