Mounting evidence implicates the Hippo downstream effectors Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) in hepatocellular carcinoma (HCC). We investigated the functional contribution of YAP and/or TAZ during c-MYC induced liver tumor development.YAP and/or TAZ requirement for c-Myc driven hepatocarcinogenesis was analyzed using conditional Yap, Taz, and Yap;Taz knockout (KO) mice. Hepatocyte-specific inducible TTR-CreERT2 KO system was applied to evaluate the role of YAP and TAZ during tumor progression. Expression patterns of YAP, TAZ, c-MYC, and BCL2L12 were analyzed in human HCC samples.We found that the Hippo cascade is inactivated in c-Myc induced mouse HCC. Intriguingly, TAZ, but not YAP mRNA levels and TAZ activation status, correlated with c-MYC activity in human and mouse HCC. We demonstrated that TAZ is a direct transcriptional target of c-MYC. In c-Myc induced murine HCCs, ablation of Taz, but not Yap, completely prevented tumor development. Mechanistically, TAZ was required to avoid c-Myc induced hepatocyte apoptosis during tumor initiation. The anti-apoptotic BCL2L12 gene was identified as a novel target regulated specifically by YAP/TAZ, whose silencing strongly suppressed c-Myc driven murine hepatocarcinogenesis. In c-Myc murine HCC lesions, conditional knockout of Taz, but not Yap, led to tumor regression, supporting the requirement of TAZ for c-Myc HCC progression.TAZ is a pivotal player at the crossroad between the c-MYC and Hippo pathways in HCC. Targeting TAZ might be beneficial for the treatment of HCC patients with c-MYC activation.We identified TAZ as a transcriptional c-MYC target and the TAZ/BCL2L12 axis as a critical anti-apoptotic effector in c-MYC dependent hepatocarcinogenesis.Copyright © 2021. Published by Elsevier B.V.