Liver cancer has been reported to be one of the most malignant diseases in the world. It is late diagnosis consequently leads to a difficult treatment, as the cancer reached an advanced stage. Hepatocellular carcinoma (HCC) is the primary type of cancer diagnosed in the liver, with deadly characteristics and a poor prognosis. The first‐in‐line treatment for advanced HCC is sorafenib. Sorafenib acts by inhibiting cell proliferation and by inducing apoptosis as well as blocks receptors associated with these mechanisms. Due to its constant use, sorafenib resistance has been described, especially to proteins of the Bcl‐2 family, and their overexpression of Bcl‐XL and Mcl‐1. This review focuses on the role of the Bcl‐2 proteins in relation to sorafenib resistance as a consequence of first‐in‐line treatment in HCC.