The hyperkeratotic, exophytic, dome shaped general wart of the skin usually represent verruca vulgaris, which occurs mainly due to infections of three important human papilloma viruses HPV-2, HPV-4, and HPV-40. The virus induced restricted growth in the superficial layer leads to sessile, verrucous, discrete papules and nodules. The virus essentially causes intraepithelial extended infectious cycle with no cell death or viraemia. At first E-genes are up regulated and after binding with syndecan-1 and TRAPPIII complex, the virus infects primitive basal keratinocytes through integrin receptors leading to combined replication of the virus and the cells. In this stage gene expressions occur with E1, E2, E6, E7 genes with latent infection and episomal viral DNA. After this, there is up regulations of both E and L genes, which leads to upstream infections in differentiated cells. The late gene expressions occur helping viral assembly and release by L1, L2, E4 gene, and finally only L gene up regulation play a key role during desquamation of viral laden squamous cells. Among cytokine genes, there are up regulations of IL6, IL8, IL10 and down regulations of IL1, IL18, IL2, TNF and IFN genes. The malignancy is mainly responsible for a crosstalk with the Hippo pathway signaling molecules and EGFR. Thus the gene expressions as well as molecular pathogenesis leading to verruca vulgaris occur in a stratified way, which is unique of this disorder. Gene expressions and synchronous viral replication in a differential cellular population is the primary foundation of verruca vulgaris and a molecular cross talk may lead to malignant transformation of this disease.