Background and Aims: Great efforts have been made towards increasing our understanding of the pathogenesis involved in hepatocellular carcinoma (HCC), but the rapid growth inherent to such tumor development remains to be explored. Methods: We identified distinct gene coex-pression modes upon liver tumor growth using weighted gene coexpression network analysis. Modeling of tumor growth as signaling activity was employed to understand the main cascades responsible for the growth. Hub genes in the modules were determined, examined in vitro, and further assembled into the growth signature. Results: We revealed modules related to the different growth states in HCC, especially the fastest growth module, which is pre-served among different HCC cohorts. Moreover, signaling flux in the cell cycle pathway was found to act as a driving force for rapid growth. Twenty hub genes in the module were identified and assembled into the growth signature, and two genes (NCAPH, and RAD54L) were tested for their growth potential in vitro. Genetic alteration of the growth signature affected the global gene expression. The activ-ity of the signature was associated with tumor metabolism and immunity in HCC. Finally, the prognosis effect of the growth signature was reproduced in nine cancers. Conclu-sions: These results collectively demonstrate the molecule organization of rapid tumor growth in HCC, which is a highly synergistic process, with implications for the future man-agement of patients.