Rabies virus, the prototypical neurotropic virus, causes one of the most lethal zoonotic diseases. According to official estimates, over 55,000 people die of the disease annually, but this is probably a severe underestimation. A combination of virulence factors enables the virus to enter neurons at peripheral sites and travel through the spinal cord to the brain of the infected host, where it often induces aggression that facilitates the transfer of the virus to a new host. This Review summarizes the current knowledge of the replication cycle of rabies virus and virus– host cell interactions, both of which are fundamental elements in our quest to understand the life cycle of rabies virus and the pathogenesis of rabies.