A poly(lactic-co-glycolic acid) (PLGA) microsphere formulation was developed which incorporates carboxylic acid groups into the microsphere surface. These functional groups are suitable for coupling to a variety of ligands and form linkages that remain stable in aqueous environments for extended periods of time. The ligand binding capacity of these microspheres compares favorably to that of similarly sized carboxylated polystyrene microspheres, which are commonly used as model particles for targeted delivery studies. Targeting microspheres to specific cell types by ligand-cell surface receptor interactions can increase the site specificity of microspheres administered intravenously or mucosally. The morphology and drug release kinetics of this PLGA microsphere formulation are not significantly different from those made with traditional reagents. This formulation allows for covalent surface modification of degradable microspheres with encapsulated payloads, which will enable studies that evaluate the ability of targeted microspheres to increase the effectiveness of payload delivery to sites of interest compared to nontargeted formulations.