Plant viruses cause severe losses in a wide range of hosts. Dissecting the molecular mechanisms behind host-virus interaction will assist in better understanding of the infection process and establishment of disease, which would lead to development of sustainable strategies for management of the virus. In addition to functional genomics, both global and specialized proteomic methods are emerging as useful approaches to study plant response to different stress factors, including plant-pathogen interactions. Various proteomic approaches such as two-dimensional gel electrophoresis (2DE), two-dimensional differential in gel electrophoresis (2D-DIGE), and yeast two-hybrid (Y2H) have been widely used to study the molecular and metabolic events during the interaction between the host and the viruses. Proteomic approaches will also help in the identification of target and disease biomarkers, which may prove to be useful for managing viral diseases and developing diagnostic tools.