The complex interplays between cytokines and chemokines are emerging as key communication signals in the shaping of innate and adaptive immune responses against foreign pathogens, including viruses. In particular, the virus-induced expression of cytokine and chemokine profiles drives the recruitment and activation of immune effector cells to sites of tissue infection. Under the conditions of infection with murine cytomegalovirus (MCMV), a herpesvirus with pathogenic potential, early immune functions are essential in the control of virus replication and virus-induced pathology. The coordinated MCMV-induced cytokine and chemokine responses promote effective natural killer (NK) cell recruitment and function, and ultimately MCMV clearance. The studies highlighted in this chapter illustrate in vivo pathways mediated by innate cytokines in regulating chemokine responses that are vital for localized antiviral defenses.