SummaryMounting an effective immune response is crucial for the host to protect itself against invading pathogens. It is now well appreciated that reprogramming of core metabolic pathways in immune cells is a key requirement for their activation and function during infections. The role of several ancillary metabolic pathways in shaping immune cell function is less well understood. One such pathway, for which interest has recently been growing, is the hexosamine biosynthesis pathway (HBP) that generates uridine diphosphate N‐acetylglucosamine (UDP‐GlcNAc), the donor substrate for a specific form of glycosylation termed O‐GlcNAcylation. O‐GlcNAc is an intracellular post‐translational modification that alters the functional properties of the modified proteins, in particular transcription factors and epigenetic regulators. An increasing number of studies suggest a central role for the HBP and O‐GlcNAcylation in dictating immune cell function, including the response to different pathogens. We here discuss the most recent insights regarding O‐GlcNAcylation and immunity, and explore whether targeting of O‐GlcNAcylation could hold promise as a therapeutic approach to modulate immune responses to infections.