Virus-specific antibodies are generally considered antiviral and play an important role in the control of virus infections in a number of ways. However, in some instances, the presence of specific antibodies can be beneficial to the virus infection. This activity is known as antibody-dependent enhancement (ADE) of virus infection. The ADE of virus infection is a phenomenon in which virus-specific antibodies enhance the entry of virus and in some cases the replication of the virus into monocytes/macrophages and granulocytic cells through interaction with Fc and/or complement receptors. This phenomenon has been reported in vitro and in vivo for viruses representing numerous families and genera of public health and veterinary importance, particularly in the dengue virus. These viruses share some common features such as preferential replication in macrophages, ability to establish persistence, and antigenic diversity. For some viruses, ADE of infection has become a great concern for disease control by vaccination. Consequently, numerous approaches have been made to the development of vaccines with minimum or no risk for ADE. Identification of viral epitopes associated with ADE or neutralization is important for this purpose. In addition, a clear understanding of the cellular events after virus entry through ADE has become crucial for developing an efficient intervention. However, the mechanisms of ADE still remain to be better understood in the case of the Japanese encephalitis virus (JEV). Hence, this chapter attempts to investigate in the context of Japanese encephalitis viral infection. The role of ADE in the pathogenesis of JEV will be discussed along with the mechanism underlying ADE and its potential risks in JE-vaccinated individuals. Furthermore, this chapter also includes insights into the sero-cross-reactivity among various flaviviruses which will be studied extensively, providing an understanding into the future perspectives of research on ADE.