A complex network of interactions exist between the innate and adaptive immune pathways, which act together to elicit a broad and durable host response following pathogen infection. The importance of the complement system in the host's defense against viruses has become increasingly clear as a result of detailed studies using transgenic mouse models that disrupt specific components of this host immune mechanism. We have utilized herpes simplex virus and replication-defective mutant strains to examine the impact of the complement system on development and maintenance of humoral immune responses. Here we review work from our group and others that highlights the central role that complement proteins C3 and C4 and complement receptors Cr1/Cr2 play during viral infection. We discuss the implications of these results in the context of pathogen infection and current vaccine strategies.