The outcome of a viral infection is the result of an endless fight between the organism whose task is to mount an antiviral response and the virus that adapts strategies to circumvent the host response. Human cytomegalovirus (HCMV), a latent herpesvirus, can be considered as a spearhead in exploiting co-existence with the host to develop numerous immuno-evasion mechanisms. The ability of the organism to initiate a primary immune response against viruses such as HCMV is highly dependent on the capacity of professional antigen-presenting cells (APCs), namely dendritic cells (DCs), to prime and activate specific effector T cells. Recent findings emerging from the murine cytomegalovirus (MCMV) animal model demonstrated that infection of murine DCs with MCMV impaired their capacity to prime an effective T cell response. Even though data on interference of HCMV with DC functions are still limited, immunosuppressive effects identical to those reported for MCMV can be suspected and we may then ask how a cytotoxic T lymphocyte (CTL) response is generated in these unfavourable conditions. In response to this question, cross-presentation of HCMV antigens by uninfected DCs to CD8+ T cells could be considered a key process in initiating an immune response. In this chapter we discuss the mechanisms through which DCs could acquire HCMV antigens and how cross-presentation could be modulated throughout infection. Moreover, further knowledge of DC functions is key for the development of DC-based immunotherapy against HCMV.