Plague is transmitted from animal to animal and from animal to human by the bites of infective fleas. Less frequently, the organism enters through a break in the skin by direct contact with tissue or body fluids of a plague–infected animal, for instance, in the process of skinning a rabbit or other animal. Plague is also transmitted by inhaling infected droplets expelled by coughing, by a person or animal, especially domestic cats, with pneumonic plague. Transmission of plague from person to person is uncommon and has not been observed in India since 1995 but does occur as an important factor in plague epidemics in some developing countries.

Fleas become infected by feeding on rodents, such as the chipmunks, prairie dogs, ground squirrels, mice, and other mammals that are infected with the bacteria Yersinia pestis. Fleas transmit the plague bacteria to humans and other mammals during the feeding process. The plague bacteria are maintained in the blood systems of rodents.