With almost 800.000 annual deaths, hepatocellular carcinoma (HCC) has the fourth highest cancer mortality rate, owed mainly to late stage diagnosis and poor response to treatment. In average, approx. 30% of cases exhibit mutations within the TP53 gene, with much higher frequencies in Africa and China, where a specific hepatitis B virus (HBV) and aflatoxin B1 (AFB1) related mutation (R249S) is present in 50% and 90% of cases, respectively, making TP53 the most frequently mutated tumor suppressor gene in HCC.Mutant p53 has a direct impact on tumorigenesis via distortion of numerous regulatory pathways, including activation of c-myc, and inactivation of TAp63, with the latter being related to initiation of a pro-invasive transcription program. Abrogation of p53-induced cell cycle arrest and apoptosis is esp. pronounced in HBV positive cases through interference of the HBx protein. Generally, TP53 mutations are related to a poor prognosis, making them an important prognostic factor. In a pilot study, an immunoprognostic model based on differential expression of immune-related genes in HCC cases with WT vs. mutant p53 was superior to clinicopathologic risk factors alone in predicting the risk of poor clinical outcome.In high-risk areas with high levels of exposure to HBV and AFB1 like Sub-Saharan Africa and China, the predominant R249S mutation can be used as biomarker for early cancer detection, assessed as circulating free DNA from peripheral blood.A new concept of a two-step therapeutic scheme specifically targets cells with mutant p53 for induction of senescence in a first step, and initiation of apoptosis in these cells in a second step. Another new approach inhibits the E3 ubiquitin ligase ARF-BP1 resulting in growth suppression and G2/M phase cell cycle arrest regardless of the TP53 status. Restoring of WT p53 activity through gene therapy is a valuable and promising approach esp. in patients without p53 expression.This review summarizes recent studies and presents their findings in one common context, interconnecting their ideas and approaches in order to markup new possible ways to tackle HCC on all levels, from surveillance, diagnosis and risk stratification to therapy.