Publisher Summary This chapter surveys the historical background to the phenomenon of antibody-dependent enhancement (ADE) of viral infectivity and considers the two mechanisms that are known to exist. It updates the earlier review of Halstead that was concerned solely with enhancement mediated by cellular receptors for the Fc portion of immunoglobulin molecules (FcR), and it extends the mini review of Porterfield and Cardosa that also took note of the second enhancement pathway mediated by receptors for components of the complement system. The first reports of ADE provide convincing documentation that the phenomenon is not an observational artifact. The studies of Halstead and collaborators were conducted against a background of the clinical problem of dengue hemorrhagic fever and the dengue shock syndrome that appeared to be unique. They also put forward the view that ADE of viral replication by non-neutralizing antibody might be a rather general biological phenomenon. The underlying concept is simple. Cells bearing receptors for the Fc portion of immunoglobulin will bind IgG. Complexes of virus and antibody will bind to the Fc receptor. If the antibody is non-neutralizing, the virus will be able to infect the FcR-bearing cell which is normally poorly permissive to viral infection. Observations in several laboratories on a wide range of different viruses have established that the phenomenon of ADE is not confined to dengue viruses. Primary macrophages carry FcR and some observations on ADE in primary macrophages in different states of activation are considered in the chapter.