Control of burst release is a major challenge in the development of poly(lactide-co-glycolide) (PLGA) microparticle drug delivery systems. It has been well-documented in previous literature that formulation and processing variables determine particle morphology, which in turn, governs drug diffusivity and burst release. However, it is not generally appreciated that PLGA polymers used for microparticle systems are typically amorphous, and as such, undergo structural relaxation during processing and storage, characterized by enthalpy and volume reduction. Volume reduction due to structural relaxation can decrease drug diffusivity within microparticles and affect burst release. The magnitude of the driving force leading to structural relaxation is linked to the rate of particle hardening, and is affected by process parameters. Studies that directly address structural relaxation in PLGA microparticles indicate that the manufacturing process and residual solvent levels, as well as the nature of the interaction between drug and polymer affect the rate of structural relaxation. Therefore, the conditions chosen for particle fabrication may be a major source of variability in the burst release and may affect the stability of the drug release profile during storage. The potential effects of structural relaxation on drug release are likely to be formulation specific. Additional work is required to understand and control the relationship between microparticle processing, structural relaxation, and performance of PLGA microparticle drug delivery systems.