Animal models that mimic human infections provide insights in virus-host interplay; knowledge that in vitro approaches cannot readily predict, nor easily reproduce. Human cytomegalovirus (HCMV) infections are acquired asymptomatically, and primary infections are difficult to capture. The gap in our knowledge of the early events of HCMV colonization and spread limits rational design of HCMV antivirals and vaccines. Studies of natural infection with mouse cytomegalovirus (MCMV) have demonstrated the olfactory epithelium as the site of natural colonization. Systemic spread from the olfactory epithelium is facilitated by infected dendritic cells (DC); tracking dissemination uncovered previously unappreciated DC trafficking pathways. The olfactory epithelium also provides a unique niche that supports efficient MCMV superinfection and virus recombination. In this review, we summarize recent advances to our understanding of MCMV infection and spread and the tissue-specific mechanisms utilized by MCMV to modulate DC trafficking. As these mechanisms are likely conserved with HCMV, they may inform new approaches for preventing HCMV infections in humans.