The components and transcriptional targets of the canonical Wnt signaling pathway are frequently altered and serve as major oncogenic drivers in hepatocellular carcinoma. Zebrafish larvae emerged as unique models for studying early stage tumorigenesis due to their small size and optical transparency. In a triple transgenic zebrafish larva, fabp10a:TetOn; TRE:GAL4-VP16 expresses the inducible transactivator TetOn via the hepatocyte-specific promoter; TRE:ABC-P2A-tcf7l2 expresses human CTNNB1 carrying four typical mutations and zebrafish tcf7l2 ectopically in the zebrafish liver; TCFSiam:mCherry, a transcriptional reporter for canonical Wnt activity, labels the Wnt-responsive cells. Meanwhile, TRE:eGFP-KrasV12 conditionally activates Ras signaling. Together, the zebrafish larva displays significant hepatomegaly and severe hyperplasia within three days in doxycycline induction, with double oncogenic pathway activated. For details, see article by Yao and colleagues on page 5548.