Many factors play into the complexity of viral pathogenesis. Understanding viral pathogenesis is key to developing vaccines and treatments for viral diseases. One emerging area of research is proteomics, which is the study of the protein complement and functions of the genome. Many different proteomic approaches have been utilized by researchers worldwide to further elucidate viral pathogenesis. For example, a high throughput MALDI-MS approach was recently employed to study the antigenicity of the influenza virus. Another study utilized MALDI-TOF MS and liquid chromatography MS/MS of proteins present in lipid droplets of hepatoma cell lines to identify proteins involved in the pathogenesis of hepatitis C virus that contribute to its carcinogenic properties. In conjugation with MS, yeast two-hybrid systems have also been shown to be useful in identifying potential host receptors of various viruses as well as revealing the interaction of viral proteins with other host proteins and viral proteins. In this review, the focus is on various proteomic approaches to dissecting the mechanisms of viral pathogenesis.