Rabies is one of the oldest diseases known to mankind. The pathogenic mechanisms by which rabies virus infection leads to development of neurological disease and death are still poorly understood. Analysis of rabies-infected proteomes may help identify novel biomarkers for antemortem diagnosis of the disease and target molecules for therapeutic intervention. This article offers a literature synthesis and critique of the differentially expressed proteins that have been previously reported from various in vitro/in vivo model systems and naturally infected clinical specimens. The emerging data collectively indicate that, in addition to the obvious alterations in proteins involved in synapse and neurotransmission, a majority of cytoskeletal proteins are relevant as well, providing evidence of neuronal degeneration. An interesting observation is that certain molecules, such as KPNA4, could be potential diagnostic markers for rabies. Importantly, proteomic studies with body fluids such as cerebrospinal fluid provide newer insights into antemortem diagnosis. In order to develop a complete integrative biology picture, it is essential to analyze the entire CNS (region-wise) and in particular, the brain. We suggest the use of laboratory animal models over cell culture systems using a combinatorial proteomics approach, as the former is a closer match to the actual host response. While most studies have focused on the terminal stages of the disease in mice, a time-series analysis could provide deeper insights for therapy. Postgenomics technologies such as proteomics warrant more extensive applications in rabies and similar diseases impacting public health around the world.