Our laboratory determined that N-glycosylation of a circulating immunoglobulin was required for receptor binding because long-range contacts within the antibody molecule stabilize key residues to form an interface with the receptor. We believe, based on these results and the high frequency of N-glycan addition to secreted proteins, that comparable mechanisms are likely found throughout the body but remain undescribed due to technological limitations. We developed a multi-technique strategy utilizing solution nuclear magnetic resonance spectroscopy, mass spectrometry, recombinant protein expression and stable isotope labeling as well as isolation and high-resolution characterization of proteins from primary human tissue to surmount this obstacle. We are currently applying and expanding this platform to identify new N-glycans that modulate protein function by focusing on the immune system where we expect to find countless more examples. A high-resolution definition of novel cell-mediated variables that affect function will provide insight into cell function and will form the foundation for future therapies to promote health and alleviate disease.