Fibroblast growth factor receptors (FGFR) are a family of four receptor tyrosine kinases (FGFR1-4) essential for cell proliferation and differentiation. FGFRs have been implicated in the development of colorectal, lung, and renal cell cancers as well as hepatocellular carcinoma and are therefore considered attractive targets for cancer therapy). 144 FIIN-2 and FIIN-3 are the first effective inhibitors of the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. 145 FIIN-2 and FIIN-3 are pyrimidopyrimidinone and pyrimidine analogs of FIIN-1, which in turn was based on a noncovalent inhibitor PD173074 resulting from rational design. Both FIIN-1 and FIIN-2 use a 4-acrylamidobenzyl group as the warhead. Unlike other dual covalent inhibitors of EGFR and VEGFR, FIIN-3 exploits a single acrylamide group that can access two spatially distinct cysteine residues, Cys797 in EGFR and Cys477 in FGFR4, respectively. 122, 147, 148 BLU554 (fisogatinib), an aminoquinazoline-based selective irreversible FGFR4 inhibitor, was designed by covalent targeting of a unique cysteine residue (Cys552) in the hinge region of FGFR4. In contrast, the other analogous residue in other family members, FGFR1/2/3. BLU554 is currently in clinical studies for the treatment of FGFR4-driven hepatocellular carcinoma. Structural modification of the pan-FGFR inhibitor BGJ398 (infigratinib) 152 led to discovery of the potent FGFR4-selective irreversible inhibitor H3B-6527 which utilizes an acrylamide moiety in the ortho-position of the aniline ring as the warhead. H3B-6527 is currently under clinical evaluation for the treatment of hepatocellular carcinoma. Furthermore, the increased activity observed with H3B-6527 in combination with CDK4/6 inhibition provides a rationale for exploration of this combination in early clinical trials. In addition, other reported selective FGFR4 inhibitors are in the early stages of development. An irreversible FGFR inhibitor, PRN1371, was developed to target a distinct cysteine residue (Cys488) found in FGFR1-4 but not in related receptor tyrosine kinases such as VEGFR2, PDGFRα, or PDGFRβ, conferring selectivity for FGFR. PRN1371 uses an acrylamide Michael acceptor as warhead and has shown promise in early clinical trials for the treatment of advanced solid tumors. To avoid the potential undesirable side effects of irreversible inhibitors and to address the rapid FGFR4 resynthesis rate in hepatocellular carcinoma cells (less than 2 h), the reversible-covalent inhibitor, FGF401 (roblitinib) was developed. Roblitinib has entered phase I/II clinical trials for the treatment of hepatocellular carcinoma and other solid tumors harboring abnormal FGFR4 signaling. Unlike irreversible inhibitors, the aldehyde group of FGF401 forms an unstable hemi-thioacetal adduct with Cys552, a distinct non-conserved cysteine of FGFR4, to achieve reversible-covalent inhibition of FGFR4 with prolonged residence time Roblitinib has entered phase I/II clinical trials for the treatment of hepatocellular carcinoma and other solid tumors harboring abnormal FGFR4 signaling. Another promising reversible covalent inhibitor currently under development is a 5-formyl-pyrrolo[3,2-b]pyridine-3-carboxamide derivative exhibiting selective single-digit nanomolar activity against both wild-type FGFR4 as well as the FGFR4V550L/M gatekeeper mutants, while sparing FGFR1/2/3. Due to its high potency and both in vitro as well as in cell-based assays, the pyrrolopyrimidinecarboxamide serves as a promising lead compound for the treatment of hepatocellular carcinoma (HCC) involving FGFR4). Recently, a dual warhead covalent inhibitor of FGFR4, CXF-009, containing two acrylamide moieties at the two ends of the molecule have been developed. CXF-009 appears to be capable of interacting with two crucial cysteine residues (Cys477 and Cys552) and represents the first dual warhead inhibitor of FGFR4. Despite the successful design of covalent inhibitors (irreversible and reversible) targeting Cys552 of FGFR4, no FGFR4-selective inhibitors have been approved by the FDA to date. There remains an urgent need to develop new selective FGFR4 inhibitors to provide a solid foundation for the effective treatment of hepatocellular carcinoma.