Biodegradable polymeric microparticles of poly(lactide-co-glycolide) (PLG) have been extensively evaluated for drug delivery and vaccine applications over the last three decades. Despite a wealth of studies on the use of PLG microparticles in vaccines through controlled release of antigens, there is no commercial PLG-based vaccine as yet. The key challenge that prevented the development of PLG microparticles as commercial vaccines was the instability of encapsulated antigen. Over the years, advancements were made towards maintaining antigen integrity during PLG microparticle preparation and sterilization. In parallel and independently, development of PLG microparticles as therapeutic commercial products established PLG with an excellent safety record in humans, and as a suitable candidate for next-generation vaccines. Through the combination of Toll-like receptor agonist encapsulation and surface adsorption of antigen, PLG microparticles can be used as a vaccine adjuvant to address unmet medical needs, such as vaccines against HIV, malaria and TB. With strategic development of PLG-based vaccines, PLG microparticles can offer advantages over the conventional vaccine adjuvants allowing commercial development of this adjuvant.