One of the most challenging issues in the delivery of therapeutic proteins from PLGA-based microparticles is the stability and complete release of the protein in its native form. This review summarizes the methods to promote the stability and in vitro release of protein from PLGA-based microparticles. Protein stability is the precondition of complete release. One way to keep protein stability is to use stabilizer or modify protein to avoid denaturation and aggregation; another way is to avoid the pro-instability environment.