Biodegradable nano/microparticles of poly(D,L-lactide-co-glycolide) (PLGA) and PLGA-based polymers are widely explored as carriers for controlled delivery of macromolecular therapeutics such as proteins, peptides, vaccines, genes, antigens, growth factors, etc. These devices are mainly produced by emulsion or double-emulsion technique followed by solvent evaporation or spray drying. Drug encapsulation, particle size, additives added during formulation, molecular weight, ratio of lactide to glycolide moieties in PLGA and surface morphology could influence the release characteristics. Encapsulation efficiency and release rates through nano/microparticle-mediated drug delivery devices can be optimized to improve their therapeutic efficacy. In this review, important findings of the past decade on the encapsulation and release profiles of macromolecular therapeutics from PLGA and PLGA-based nano/microparticles are discussed critically in relation to nature and type of bioactive molecule, carrier polymer and experimental variables that influence the delivery of macromolecular therapeutics. Even though extensive research on biodegradable microparticles containing macromolecular drugs has greatly advanced to the level of production know-how, the effects of critical parameters influencing drug encapsulation are not sufficiently investigated for nano-scaled carriers. The present review attempts to address some important data on nano/microparticle-based delivery systems of PLGA and PLGA-derived polymers with reference to macromolecular drugs.