Early diagnosis of hepatocellular carcinoma (HCC) in nodules smaller than 2 cm detected by screening ultrasounds becomes essential given that, at that stage, no vascular invasion is usually detected and treatment is associated with a high rate of long-term survival. Improvements in imaging techniques in the last few years have allowed a conclusive diagnosis of HCC in these small nodules without invasive procedures. However, a conclusive diagnosis of HCC by imaging is not always possible and, in more than half of cases, biopsy is needed. On the other hand, histological confirmation of HCC in such tiny nodules is very complex, and in most cases impossible because of the limited sample obtained. In addition, serum tumor markers currently available show low accuracy and are useless for early diagnosis. Progress in the knowledge of molecular mechanisms associated with malignant transformation will allow the use of new techniques that will facilitate diagnosis for HCC in very early stages.