Albeit the removal of Asn297 glycans of IgG perturbs the overall conformation and flexibility of the IgG CH2 domain, resulting in the loss of Fc–ligand interactions and therapeutically critical immune effector functions, aglycosylated full-length IgG antibodies are nearly identical to the glycosylated counterparts in terms of antigen binding, stability at physiological or low temperature conditions, pharmacokinetics, and biodistribution. To bypass the drawbacks of glycosylated antibodies that include glycan heterogeneity and requirement of high capital investment for biomanufacturing, aglycosylated antibodies have been developed and several are under clinical trials. Comprehensive cellular and bioprocess engineering has enabled to produce highly complex aglycosylated IgGs in a simple bacterial cultivation with comparable production level as that of mammalian cells. Moreover, extensive engineering of aglycosylated Fc has converted the aglycosylated IgG antibodies into a new class of effector functional human immunotherapeutics.