Abstract: The viral infection-associated cytokine storm is closely associated with the poor prognosis of the critical patients, the granulocyte-macrophage colony-stimulating factor(GM-CSF) is abnormally upregulated under pathological state after viral invasion, which then may result in cytokine storm by activating multiple signaling pathways such as phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway (PI3K-AKT), mitogen-activated protein kinase-extracellular signal-regulated kinase (MAPK-ERK) signaling pathway, nuclear factor κB (NF-κB) signaling pathway and Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. In addition to the direct infection, viral binding to specific receptors enhances the replication, with factors like psychological stress and co-infections exacerbating the inflammation. GM-CSF synergizes with other cytokines to amplify the systemic inflammatory responses. The targeting GM-CSF and the targeted therapy of its downstream pathways have potential value of clinical intervention. Notably, the GM-CSF signal regulating also has direct impact on the macrophage polarization, therefore, promoting a shift to the M2 phenotype polarization represents a promising anti-inflammatory strategy.