Yersinia pestis is a highly virulent bacterial pathogen with remarkable abilities to disseminate in a host. The ability of this Gram-negative bacterium to spread and replicate in its host results in high morbidity and mortality in humans. Bubonic plague is the most prevalent form of the disease and develops after Y. pestis is deposited into the skin of a susceptible host. Little is known about the events that occur after inoculation into the skin and that result in movement of bacteria to the lymph node that drains this site. Similar questions surround how the bacteria progress beyond the lymph node to survive systemically. This work focused on the use of a murine model and a fully virulent strain of plague to gain insights into how Y. pestis interacts with the host during dissemination. We describe an imaging approach to study bacterial dissemination in mice (Chapter 2). In this chapter, a bioluminescent strain of Y. pestis was used to track bacterial spread in mice by bioluminescence imaging using different routes of infection. We also studied the major events that define dissemination from the skin into the lymph node and that result in systemic dissemination (Chapter 3). We found that dissemination of Y. pestis into lymph nodes is restricted by a bottleneck that defines the final population that colonizes the host. By using confocal microscopy, we tracked bacteria at different stages of infection and identified important sites where host-pathogen interactions occur. Lastly, we established the importance of an intradermal model of inoculation we implemented after comparing it with a subcutaneous model that has been traditionally used in the field (Chapter 4). Our study contributes significantly to the understanding of host-pathogen interaction during bacterial infections. More specifically, our findings provide important information that advances our knowledge on Y. pestis pathogenesis and how the bacterium disseminates inside a host. Because of the scope of our research, these findings have relevant implications to fields as diverse as bacterial pathogenesis, cutaneous immunity, and vaccine development.