Hepatocellular carcinoma (HCC) is one of the most lethal cancers, affecting many populations globally. It is driven by various factors, including chronic hepatitis B and C infections, alcohol consumption, and aflatoxin B1 exposure. HCC is the most common type of liver cancer, accounting for 83% of all cases. The pathogenesis of HCC involves complex interactions between host and viral factors, as well as environmental influences. Viral-induced hepatocarcinogenesis, such as that caused by HBV and HCV, involves processes like host-viral interactions, sustained cycles of necrosis-inflammation-regeneration, and viral integration into the host genome. HCV-induced hepatocarcinogenesis is associated with immune evasion and cirrhosis. Alcohol-induced hepatocarcinogenesis is linked to inflammation, oxidative stress, and cirrhosis, while aflatoxin B1-induced hepatocarcinogenesis is associated with carcinogenic mutations. Genetic events such as p53 inactivation, β-catenin mutations, and overexpression of ErbB receptors and MET are involved in HCC development. Genomic instability is a common feature of HCC, with various mechanisms contributing to it, including telomere erosion and chromosomal abnormalities. Genomic alterations in HCC include frequent gains in 1q, 6p, 8q, 11q, and 17q, and losses in 1p, 4q, 8p, 13q, and 17p. Gene-expression analyses have led to the molecular classification of HCC based on prognosis, aetiology, and recurrence. Challenges include understanding the mechanisms of genomic instability, host-viral interactions, and identifying biomarkers for early detection. Opportunities include developing targeted therapies and improving diagnostic tools. HCC is a complex disease with diverse aetiologies, and further research is needed to understand its molecular basis and develop effective treatments.Hepatocellular carcinoma (HCC) is one of the most lethal cancers, affecting many populations globally. It is driven by various factors, including chronic hepatitis B and C infections, alcohol consumption, and aflatoxin B1 exposure. HCC is the most common type of liver cancer, accounting for 83% of all cases. The pathogenesis of HCC involves complex interactions between host and viral factors, as well as environmental influences. Viral-induced hepatocarcinogenesis, such as that caused by HBV and HCV, involves processes like host-viral interactions, sustained cycles of necrosis-inflammation-regeneration, and viral integration into the host genome. HCV-induced hepatocarcinogenesis is associated with immune evasion and cirrhosis. Alcohol-induced hepatocarcinogenesis is linked to inflammation, oxidative stress, and cirrhosis, while aflatoxin B1-induced hepatocarcinogenesis is associated with carcinogenic mutations. Genetic events such as p53 inactivation, β-catenin mutations, and overexpression of ErbB receptors and MET are involved in HCC development. Genomic instability is a common feature of HCC, with various mechanisms contributing to it, including telomere erosion and chromosomal abnormalities. Genomic alterations in HCC include frequent gains in 1q, 6p, 8q, 11q, and 17q, and losses in 1p, 4q, 8p, 13q, and 17p. Gene-expression analyses have led to the molecular classification of HCC based on prognosis, aetiology, and recurrence. Challenges include understanding the mechanisms of genomic instability, host-viral interactions, and identifying biomarkers for early detection. Opportunities include developing targeted therapies and improving diagnostic tools. HCC is a complex disease with diverse aetiologies, and further research is needed to understand its molecular basis and develop effective treatments.