In order to evade host immunity, many bacteria secrete immunomodulatory enzymes. Streptococcus pyogenes, one of the most common human pathogens, secretes unique endoglycosidases, EndoS and EndoS2, which remove biantennary complex- and high mannose-type carbohydrates in a highly specific manner from human IgG antibodies. This renders antibodies incapable of eliciting host effector functions through either complement or Fc γ receptors (FcγRs), providing the bacteria with a survival advantage. Because antibodies are central players in many human immune responses and bridge the innate and adaptive arms of immunity, the analysis and manipulation of the enzymatic activity of EndoS/EndoS2 impacts diverse fields in biomedicine. In particular, modifying antibody glycan structures can have significant impacts on their abilities to bind to FcγRs and the subsequent immune system reactions that they induce. The next generation of therapeutic antibodies is already being constructed with modified glycan chemistries to tailor the immune reactions to increase their clinical potency. EndoS and EndoS2, and glycosynthases derived thereof, are key enzymes in the future of antibody engineering. We recently determined the X-ray crystal structures of EndoS and EndoS, alone and in complex with various glycans, which now provides a roadmap with which to overcome many of the current antibody engineering limitations of such enzymes.