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The hyphal development of Candida albicans(C. albicans) has been considered as an essential virulent factor for host cell damage. However, the missing link between hyphae and virulence of C. albicansis also been discovered. Here, we identified that the null mutants of ERG3and ERG11, two key genes in ergosterol biosynthesis pathway, can form typical hyphae but failed to cause the oral mucosal infection in vitro and in vivo for the first time. In particular, the erg3Δ/Δand erg11Δ/Δstrains co-cultured with epithelial cells significantly reduced the adhesion, damage, and cytokine (interleukin-1α (IL-1α)) production, whereas the invasion was not affected in vitro. Importantly, they were incapable of extensive hyphal invasion, formation of micro-abscesses, and tongue epithelium damage compared to wild type due to the decrease of the colonization and epithelial infection area in a murine oropharyngeal candidiasis model. The fluconazole (FLC), an antifungal targeted at ergosterol biosynthesis, relieved the epithelial infection of C. albicansin vitro and in vivo even under non-growth inhibitory dosage confirming the virulent contribution of ergosterol biosynthesis pathway. The erg3Δ/Δand erg11Δ/Δstrains were cleared by macrophages similar to wild type, whereas their virulence factors including agglutinin-like sequence 1 (Als1), secreted aspartyl proteinase 6 (Sap6), and hyphal wall protein-1 (Hwp1) were significantly reduced indicated that the non-toxicity might not result from the change on immune tolerance but the defective virulence. The incapacity of erg3Δ/Δand erg11Δ/Δin epithelial infection highlights the contribution of ergosterol biosynthesis pathway to C. albicanspathogenesis and fluconazole can not only eliminate the fungal pathogens but also reduced their virulence even at low dosage. The damage from oral infection with the fungus Candida albicans can be contained by targeting two cell membrane-building genes. C. albicans cells transition from a rounded shape into long filamentous structures called hyphae prior to invading and damaging host epithelial cells. Researchers led by Lei Cheng at Sichuan University have now identified a key intermediate step between hyphae formation and virulence. They determined that fungal cells lacking either of two genes that manufacture ergosterol, a component of the C. albicans membrane, still form hyphae and attach to epithelial cells. However, these mutant fungi inflict no cellular damage, and did not cause disease in mice. Furthermore, treatment with low-dose fluconazole, a drug that inhibits ergosterol synthesis, rendered the fungus non-virulent without killing it, indicating that this pathway represents an important ‘missing link’ for fungal pathogenesis.