Exciting developments have been made in understanding antibody-mediated immunity, deepening understanding of antibody effector functions increasingly recognized as critical mechanisms of action beyond antigen recognition, and significantly broadening the evidence base for the importance of these effector mechanisms across diverse infectious and autoimmune diseases. Because these activities critically depend on the specific glycoforms present on a conserved site of the IgG Fc domain, relationships between the Fc glycosylation profiles of antigen-specific antibody pools and outcomes in infectious and autoimmune disease have begun to be defined, pointing to the key role of this posttranslational modification as a biomarker and mechanistic modifier of antibody-mediated immunity. Here we summarize studies evaluating the profiles and activities of antigen-specific antibodies elicited by infection and vaccination as well as within the context of allo- and autoimmunity, and consider current approaches to rational modification of Fc glycans in vivo.