Sialic acid sugars are vital regulators of the immune system through binding to immunosuppressive sialic acid-binding immunoglobulin-like lectin (Siglec) receptors on immune cells. Aberrant sialic acid-Siglec interactions are associated with an increasing number of pathologies including infection, autoimmunity, and cancer. Therefore, the sialic acid-Siglec axis is an emerging target to prevent or affect the course of several diseases. Chemical modifications of the natural sialic acid ligands have led to sialic acid mimetics (SAMs) with improved binding affinity and selectivity towards Siglecs. Recent progress in glycobiotechnology allows the presentation of these SAMs on nanoparticles, polymers, and living cells via bioorthogonal synthesis. These developments now enable the detailed study of the sialic acid-Siglec axis including its therapeutic potential as an immune modulator.