Infection occurs when the virus gains access to the body, usually though a bite wound, though contact of affected saliva on an open wound or mucosal surface may also occur (such as inhalation of virus laden particles in caves frequented by bats). The virus then incubates at the site of inoculation usually replicating within muscle cells. After an extended incubation time the virus gains entry to nerves and travels by retrograde axonal flow toward the central nervous system - first to the spinal cord then to the brain, except in cases of innoculation into or near a cranial nerve.  Once in the brain the virus travels by axonal flow down the trigeminal nerve to the salivary glands. The virus is usually present in the saliva and the animal infective 3-5 days prior to the onset of clinical signs.

As the virus first incubates in the site of inoculation, usually in muscle cells and then travels through the peripheral nerves by retrograde axonal flow to the central nervous system, the length of time until development of clinical signs is in part related to the distance the virus must travel. Hence, a bite to a distal periphery will have a longer incubation period than a bite to the face. This provides time for post-exposure vaccination to work, even if prior vaccination had not occurred.

In dogs, the normal incubation period is 21-80 days, though it can be shorter or much longer depending on the location of the bite.  One reported human case had an incubation of more than 6 years (Merck Veterinary Manual, Smith et al. 1991)

Initially there is little immune response, though an antibody respose does develop as clinical signs progress, however at this point it is too late for antibodies to have an effect, as the virus is already within the central nervous system which is well protected by the blood-brain barrier, and hence has no exposure to antibodies. 

As the virus invades farther into the CNS there is an increase in nervous signs, causing either the raging of dumb forms (or some combination thereof) depending on the animal and what parts of the brain are affected as well as the source of the virus.  Furious symptoms result from changes to the limbic system and the dumb form results from changes to the neocortex.  Death results from respiratory paralysis from the virus affecting the breathing centres.  Other signs such as excitement, salivation, and increased sexual activity result from the effects on the autonomic nervous system.  In advanced disease there are viral inclusion bodies "Negri bodies" found in nearly all neurons within the brain (though the supporting cells are not affected).